CN102718708A - Novel nitrogen-containing heteroaryl compounds and methods of use thereof - Google Patents

Novel nitrogen-containing heteroaryl compounds and methods of use thereof Download PDF

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CN102718708A
CN102718708A CN2012101526867A CN201210152686A CN102718708A CN 102718708 A CN102718708 A CN 102718708A CN 2012101526867 A CN2012101526867 A CN 2012101526867A CN 201210152686 A CN201210152686 A CN 201210152686A CN 102718708 A CN102718708 A CN 102718708A
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isoquinoline
hydroxyl
amino
carbonyl
acetate
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迈克尔·P·阿兰德
李·A·弗利平
福尔克马·京茨勒-普卡尔
何文彬
埃里克·D·图尔托
杜晓辉
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Fibrogen Inc
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Fibrogen Inc
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Abstract

The present invention relates to compounds suitable for use in mediating hypoxia inducible factor and for treating erythropoietin-associated conditions by increasing endogenous erythropoietin in vitro and in vivo.

Description

Contain azaheteroaryl and the purposes in increasing endogenous erythropoietin thereof
The cross reference of related application
No. the 60/476th, 811, the U.S. Provisional Patent Application case of the application's case opinion application on June 6th, 2003; The 60/476th, No. 420 of on June 6th, 2003 application; The 60/476th, No. 633 of on June 6th, 2003 application; The 60/476th, No. 519 right under United States Code the 35th volume the 119th (e) bar with application on June 6th, 2003; The full text of all said application cases is incorporated herein by reference.
Technical field
The present invention relates to regulate the stability and the method and the compound that increase endogenous erythropoietin in external and the body of hypoxia inducible factor (HIF) alpha subunit.
Background technology
An early response of histanoxia is inducing of hypoxia inducible factor (HIF); Hypoxia inducible factor is the agent of a kind of alkaline helix-loop-helix (bHLH) PAS (Per/Arnt/Sim) transcriptional activation, and its regulation and control are with the change of the genetic expression of cell oxygen concn change.HIF is a kind of heterodimer that an oxygen is regulated an alpha subunit (HIF α) and a constructive expression β subunit (HIF β) that contains, and also is called as aryl hydrocarbon receptor nuclear translocation albumen (ARNT).In oxygenate (normal oxygen) cell, the mechanism rapidly degraded of HIF alpha subunit through relating to retinal blood tuberculation (von Hippel-Lindau tumor) arrestin (pVHL) E3 ligase enzyme mixture ubiquitinization.Under anoxia condition; HIF α does not degrade; And a kind of active HIF α/beta composite is accumulated in nucleus and is activated some expression of gene, comprises glycolytic ferment, GLUT (GLUT)-1, erythropoietin (EPO) and vascular endothelial growth factor (VEGF).(people such as Jiang, (1996) " journal of biological chemistry " (J.Biol.Chem.), 271: 17771-17778; People such as Iliopoulus, (1996) " PNAS " (Proc.Natl.Acad.Sci.USA), 93: 10595-10599; People such as Maxwell, (1999) " nature " (Nature), 399: 271-275; People such as Suiter, (2000) " PNAS ", 97: 4748-4753; People such as Cockman, " journal of biological chemistry ", 275: 25733-25741; With people such as Tanimoto, (2000) " European molecular biology journal " (EMBO.J.) 19: 4298-4309).
In most cells, the proteic content of HIF α improves with anoxic, and when animal suffers from anaemia or anoxic, induces HIF α in the body.In the several hrs after anoxic begins, the content of HIF α raises and is continuing to get back to baseline under the anoxia condition.HIF has related in numerous cell evolutions, comprises cell proliferation, vasculogenesis and cell cycle arrest.HIF α also with myocardium acute ischemia and early stage infraction, pulmonary hypertension and inflammation-related.Although HIF α has a little sign to represent that HIF directly relates to tumour and takes place with tumor growth and shift relevantly.The anoxic pre-treatment has shown can protect cardiac muscle and brain not to receive anoxic-ischemic damage, and wherein target organ suffers from the short-term anoxic.The stability of HIF α and local asphyxia are closely related and pass through pretreatment induction.(Wang and Semenza, (1993) " PNAS ", 90: 4304-4308; People such as Stroka, (2001) " the U.S. biomedical association of experiment journal (FASEB.J.), 15: 2445-2453; People such as Semenza, (1997) " international kidney journal (Kidney Int.), 51: 553-555; People such as Carmeliet, (1998) " nature " 394: 485-490; People such as Zhong, (1999) " cancer research journal (Cancer Res.), 59: 5830-5835; People such as Lee, (2000) " New England Journal of Medicine " (N.Engl.J.Med.), 343: 148-149; People such as Sharp, (2000) " cerebral blood flow and metabolism journal (J.Cereb.Blood Flow Metab.), 20: 1011-1032; People such as Semenza, (2000) " experimental medicine and biology progress " (Adv.Exp.Med.Biol.), 475: 123-130; People such as Thornton (2000) " journal of biological chemistry " (Biochem.J.), 350: 307-312; Deindl and Schaper, (1998) " molecule and cellular biochemistry " (Mol.Cell.Biochem.), 186: 43-51; People such as Bergeron, (2000) " neuroscience annual report " (Ann.Neurol.), 48: 285-296).
Some investigators study the interaction mechanism between HIF α and the pVHL.Think that at first the interior oxygen dependence property degraded territory (ODD) from residue 401 to 603 of HIF-1 α is enough to give chimeric protein structure oxygen dependence unstable.What it is found that the degraded of pVHL dependency need be from residue 526 to 652 contains the proteic territory of ODD.On the other hand, P564YI sports aspartic acid or K532 and sports l-arginine and make under normal oxygen condition the degraded that whole body HIF α is protein stabilized and opposing is mediated by pVHL in the zone in being stored in HIF alpha homologues (residue 556 to 574 among the HIF-1 α).(people such as Huang, (1998) " PNAS ", 95: 7987-7992; With people such as Tanimoto, (2000) " European molecular biology journal ", 19: 4298-4309).
The HIF alpha content increases through many simulation anoxic factors, comprises iron chelating agent, for example desferrioxamine (DFO) and divalent metal, for example CoCl 2The HIF alpha content is under normal oxygen condition, to utilize the mechanism that relates to active oxygen to increase through Angiotensin II, zymoplasm and Thr6 PDGF BB.Report also proposes, and HIF α regulates through phosphorylation, its via relate to nitrogen protoxide activated PI 3 '-path of kinases (PI3K), pHGF or mitogen activated protein kinase.The direct phosphorylation HIF α of glycogen synthase kinase ODD territory as the downstream target thing of PI3K.(people such as Richard, (2000) " journal of biological chemistry " (J.Biol.Chem.), 275: 26765-26771; People such as Sandau, (2000) " biological chemistry and biophysical research communication " (Biochem.Biophys.Res.Commun.), 278: 263-267; People such as Tacchini, (2001) " the carcinogenic journal of molecule (Carcinogenesis), 22:1363-1371; With people such as Sodhi, (2001) " biological chemistry and biophysical research communication ", 287: 292-300).
Erythropoietin (EPO) is a kind of hormone that exists naturally that produces with HIF α, and it stimulates delivery oxygen to run through the generation of the red corpuscle (red blood corpuscle) of whole body.EPO is usually by renal secretion, and endogenous EPO increases under the condition of oxygen minimizing (anoxic).The all types anaemia is characterised in that the ability of blood delivery oxygen reduces, and thereby with similar sign and symptom, comprise skin and mucosal pallor, weakness, dizziness, fatiguability and drowsiness, cause the decline of quality of life.Experimenter with serious anaemia situation shows and is difficult to breathe and heart malformations.Anaemia usually with red corpuscle in or in the oxyphorase the leiphemia patient's condition relevant.
The common reason of anaemia comprises iron, vitamins B 12And folic acid deficiency.Anaemia also can be concurrent with chronic disease, and for example inflammatory conditions comprises illness with the inhibition of secondary marrow inflammatory or the like.Anaemia can cause by losing blood, for example because accident, operation or by the drug-induced gastrointestinal hemorrhage of for example Frosst) and Ibuprofen BP/EP.Excessively lose blood and also be found among the women who goes out hyperhematosis menstrual period and contain among the crowd of stomach ulcer, duodenal ulcer, hemorrhoid or cancer of the stomach or large bowel cancer etc.
Multiple condition can cause erythrocytic destruction (haemolysis), thereby causes anaemia.For example, can cause haemolysis to the anaphylactic type reaction of bacteriotoxin and number of chemical reagent, for example sulfamido and benzene.Hemolytic anemia is often caused by chemical poisoning, parasite, infection or sicklemia.In addition, there is abnormal case, health himself the erythrocytic antibody that creates antagonism wherein, thus cause haemolysis.Any bone marrow disease or damage can cause anaemia, generate because this tissue is a red blood corpuscle, i.e. red blood corpuscle synthetic place.Radiation, disease or number of chemical reagent can cause that also marrow destroys, and produces aplastic anemia.Experience chemotherapeutic cancer patients and often have aplastic anemia.Anaemia is also relevant with renal tubal dysfunction, the seriousness of anaemia and handicapped degree height correlation.Most of patients with renal failure of experience dialysis suffer from chronic anaemia.
Except in kidney, producing, erythropoietin also produces in central nervous system (CNS) through stellate cell and neurone, and EPO and EPO acceptor are expressed on the kapillary at interface, brain periphery.In addition, the EPO of whole body dispensing passes through hemato encephalic barrier and reduces the neurocyte loss that produces with brain and spinal cord local asphyxia, mechanical injury, epilepsy, excitotoxin and neural inflammation.(Sakanaka, (1998) " PNAS ", 95: 4635-4640; People such as Celik, (2002) " PNAS ", 99: 2258-2263; People such as Brines, (2000) " PNAS ", 97: 10526-10531; People such as Calapai, (2000) " European pharmacology journal (Eur.J.Pharmacol.), 401: 349-356; With people such as Siren, (2001) " PNAS ", 98: 4044-404).
In the recent eighties, Amgen proposes a kind of genetic engineering EPO that is used to treat the anaemia of chronic renal failure patients.Also EPO is thrown and give experience radiation and/or chemotherapeutic cancer patients, to reduce its needs for blood transfusion.EPO is used for treatment to be infected or the relevant anaemia of Zidovodine (AZT) therapy with HIV.Although the market of EPO therapy is cumulative, following sale of expensive influence unfriendly of this product.In addition, the recombinant epo therapy needs intravenously EPO dispensing 1 to 3 time weekly, and nearly 12 weeks, the regimen restriction is offerd medicine voluntarily and the patient is brought inconvenience.On the other hand, no longer produce in any recombinant human EPO owing to extensively reach the glycosylation that changes, old friend's class serum EPO shows big or small ununiformity.
The anoxic patient's condition of inducing HIF α to produce is that a kind of oxygen reduces state, and it can take place when lung damage or blood flow minimizing.Local asphyxia (blood flow minimizing) can cause by artery or vein obstruction, and said obstruction is by clot (thrombus) or by any external recycled material (embolus) or by vascular disorder, for example atherosclerosis causes.Blood flow reduces and can begin suddenly and the time length short (acute ischemic), or can slowly begin but longer duration or frequently generation (chronic local asphyxia) again.Acute ischemic is normal and local, irreversible tissue necrosis (a kind of infarct) is relevant, yet chronic local asphyxia is often damaged relevant with transience oxygen-starved tissue.Yet if perfusion reduces prolongation or serious, chronic local asphyxia also can be relevant in infarct.Infraction generally betides spleen, kidney, lung, brain and the heart, produces illness, for example intestinal obstruction, lung infraction, ishemic stroke and myocardial infarction.
The pathological change of ischemic conditions is looked ischemic time length and seriousness, and the patient is survived length and decided.Downright bad also being found in preceding 24 hours of infraction, and acute inflammatory response takes place in the living tissue of contiguous infraction, and white corpuscle is to the necrotic tissue zone migration simultaneously.Experience several days subsequently, decompose gradually and remove the infraction inner cell through phagolysis, and replace with collagen scar or neuroglia scar.
Hypoperfusion in organ or infraction often influence other organ.For example, the lung local asphyxia that is caused by pulmonary infarction not only influences lung, and the heart and other organ (for example brain) are under the anoxybiotic pressure.Myocardial infarction can cause congestive heart failure and systemic hypertension, and it is usually directed to because the coronary occlusion that thrombosis, ductus arteriosus wall spasm or heart trouble toxinfection cause.If asystolia prolongs and continues hypoperfusion, then secondary complication can take place, for example the global ischemia encephalopathy (HIE).The most general owing to atherosclerosis causes that the cerebral ischaemia that vascular occlusion causes can be by transient ischemic attack (TIA) to cerebral infarction or apoplexy on seriousness.Though the symptom of TIA is temporary transient and reversible, TIA trends towards recurrence and often then is apoplexy.
Arteriosclerosis obliterans comprises the coronary artery disease that can cause myocardial infarction, and can influence aorta abdominalis, the peripheral arterial disease of its main branch and leg artery.The peripheral arterial disease comprises Buerger's disease (Buerger ' s disease), Raynaud disease (Raynaud ' s disease) and acrocyanosis.Although the peripheral arterial disease is caused by atherosclerosis that generally other major cause comprises for example mellitus etc.Comprise serious shank spasm, stenocardia, irregular pulse, heart failure, heart trouble, apoplexy and renal failure with peripheral arterial disease complications associated with arterial system.
Local asphyxia and anoxic illness are morbidity and main causes of death.Cardiovascular diseases causes at least one 15,000,000 dead every year and is the reason that causes the whole world 30% dead.In multiple cardiovascular diseases, ischemic heart disease and cerebro-vascular diseases cause about 17% death.Annual report has the case of 1,300,000 non-lethal Acute Myocardial Infarctions, constitutes approximately per 100,000 philtrums, 300 people's sickness rate.On the other hand, estimating has 5,000,000 Americans to suffer from phlebothrombosis disease every year, and about 600,000 these cases cause pulmonary infarction.About 1/3rd pulmonary infarction patient is finally dead, makes pulmonary infarction become the common reason of American dead the 3rd.
Current, local asphyxia and anoxic treatment of conditions concentrate on symptom alleviate with pathogenic treatment of conditions on.For example, the treatment of myocardial infarction comprises in order to pain management and the pannonit and the anodyne that alleviate the heart working load.Use other medicines; Comprise that digoxin (digoxin), diuretic(s), amrinone (amrinone), beta blocker, lipid lowering agent and angiotensin converting enzyme inhibitor stablize the patient's condition, but none can directly act on the tissue damage that is produced by local asphyxia and anoxic in these therapies.
Produce and use the deficiency in the recombinant epo owing to reach in the current treatment; So still need effectively treat the compound of following disease: the erythropoietin related conditions; Anaemia for example; Comprise the anaemia relevant and relate to local asphyxia and the anoxybiotic patient's condition, for example arteriosclerosis obliterans, stenocardia, intestinal obstruction, lung infraction, cerebral ischaemia and myocardial infarction with mellitus, anaemia, ulcer, renal failure, cancer, infection, dialysis, operation and chemotherapy.The compound of the tissue damage that also need effectively prevent to be caused by local asphyxia, said local asphyxia is owing to for example lung's illness of atherosclerosis, mellitus and for example pulmonary infarction and similar conditions thereof takes place.In a word, in this technology, need to regulate HIF and/or endogenous erythropoietin, and can be used for treating and the method and the compound that prevent the relevant and EPO associated conditions of HIF, said illness comprises and relates to anaemia, local asphyxia and the anoxybiotic patient's condition.
Summary of the invention
The present invention relates to the compounds and the method for adjustable hypoxia inducible factor (HIF) and/or endogenous erythropoietin (EPO).
An aspect of The compounds of this invention provides the compound of being represented by formula I:
Figure BDA00001645958400051
Wherein:
Q is 0 or 1;
P is 0 or 1;
R aBe-COOH or-WR 8Restricted condition is for working as R aDuring for-COOH, p is 0 and works as R aFor-WR 8The time p be 1;
W is selected from the group that is made up of following each base: oxygen ,-S (O) n-with-NR 9-, wherein n is 0,1 or 2, R 9Be selected from by following each group of forming of base: hydrogen, alkyl, through substituted alkyl, acyl group, aryl, through substituted aryl, heteroaryl, through substituted heteroaryl, heterocycle and through substituted heterocycle and R 8Be selected from by following each group of forming of base: hydrogen, alkyl, through substituted alkyl, aryl, through substituted aryl, heteroaryl, through substituted heteroaryl, heterocycle and through substituted heterocycle, perhaps work as W and be-NR 9-time, R 8And R 9Can be connected to form heterocycle or through substituted heterocycle together with its bonded nitrogen-atoms, restricted condition is for as W being-S (O) n-and n be 1 or 2 o'clock, R 8Be not hydrogen;
R 1Be selected from the group that forms by following each base: hydrogen; Alkyl; Through substituted alkyl; Alkoxyl group; Through substituted alkoxy; Amino; Through substituted-amino; Aminoacyl; Aryl; Through substituted aryl; Halogen; Heteroaryl; Through substituted heteroaryl; Heterocycle; Through substituted heterocycle; And-XR 6, wherein X be oxygen ,-S (O) n-or-NR 7-, wherein n is 0,1 or 2, R 6Be selected from by following each group of forming of base: alkyl, through substituted alkyl, aryl, through substituted aryl, heteroaryl, through substituted heteroaryl, heterocycle with through substituted heterocycle, and R 7Be hydrogen, alkyl or aryl, perhaps as X be-NR 7-time, R 7And R 8Can be connected to form heterocycle or through substituted heterocyclic radical together with its bonded nitrogen-atoms;
R 2And R 3Independently be selected from the group that forms by following each base: hydrogen; Alkyl; Through substituted alkyl; Aryl; Through substituted aryl; Heteroaryl; Through substituted heteroaryl; Halogen; Hydroxyl; Cyanic acid;-S (O) n-N (R 6)-R 6, wherein n is 0,1 or 2;-NR 6C (O) NR 6R 6-XR 6, wherein X be oxygen ,-S (O) n-or-NR 7-, wherein n is 0,1 or 2, each R 6Independently be selected from by following each group of forming of base: hydrogen, alkyl, through substituted alkyl, aryl, through substituted aryl, naphthenic base, through substituted cycloalkyl, heteroaryl, through substituted heteroaryl, heterocycle with through substituted heterocycle, restricted condition for working as X is-SO-or-SO 2-time, R 6Be not hydrogen, and R 7Be selected from the group that forms by following each base: hydrogen, alkyl, aryl, perhaps R 2, R 3Form through the substituted aryl of aryl, heteroaryl or through substituted heteroaryl together with side joint carbon atom on it;
R 4And R 5Independently be selected from the group that forms by following each base: hydrogen; Halogen; Alkyl; Through substituted alkyl; Alkoxyl group; Through substituted alkoxy; Aryl; Through substituted aryl; Heteroaryl; Through substituted heteroaryl; And-XR 6, wherein X be oxygen ,-S (O) n-or-NR 7-, wherein n is 0,1 or 2, R 6Be selected from by following each group of forming of base: alkyl, through substituted alkyl, aryl, through substituted aryl, heteroaryl, through substituted heteroaryl, heterocycle with through substituted heterocycle, and R 7Be hydrogen, alkyl or aryl, perhaps as X be-NR 7-time, R 7And R 8Can be connected to form heterocycle or through substituted heterocyclic radical together with its bonded nitrogen-atoms;
R is selected from the group that is made up of hydrogen, deuterium and methyl;
R ' is selected from by hydrogen, deuterium, alkyl and the group that forms through substituted alkyl; Perhaps, R and R ' and side joint carbon on it can be connected to form naphthenic base, through substituted cycloalkyl, heterocycle or through substituted heterocyclic radical;
R " is selected from the group or the R that are made up of hydrogen and alkyl " and can be connected to form heterocycle or through substituted heterocyclic radical together with R ' and side joint nitrogen on it;
R ' " be selected from by following each group of forming of base: hydroxyl, alkoxyl group, through substituted alkoxy, acyloxy, cycloalkyloxy, through substituted cyclo alkoxy, aryloxy, through substituted aryloxy, heteroaryloxy, through substituted heteroaryloxy, aryl ,-S (O) n-R 10R wherein 10Be selected from by following each group of forming of base: alkyl, through substituted alkyl, naphthenic base, through substituted cycloalkyl, aryl, through substituted aryl, heteroaryl with through substituted heteroaryl, and n is 0,1 or 2;
And pharmaceutically acceptable salt, ester and prodrug;
Restricted condition is as R, R ' and R, and " be hydrogen, q is 0, R aFor-COOH (p is 0) or-WR 8(p is 1), W is oxygen and R 8During for hydrogen, at least a situation below then taking place:
1) R 1For fluorine-based; Bromo; Iodo; Alkyl; Through substituted alkyl; Alkoxyl group; Aminoacyl; Through substituted alkoxy; Aryl; Through substituted aryl; Heteroaryl; Through substituted heteroaryl; Heterocycle; Through substituted heterocycle; And-XR 6, wherein X is an oxygen;-S (O) n-or-NR 7-, wherein n is 0,1 or 2, R 6Be selected from by following each group of forming of base: alkyl, through substituted alkyl, aryl, through substituted aryl, heteroaryl, through substituted heteroaryl, heterocycle with through substituted heterocycle, and R 7Be hydrogen, alkyl or aryl; Or
2) R 2For through substituted alkyl; Aryl; Through substituted aryl; Heteroaryl; Through substituted heteroaryl; Fluorine-based; Bromo; Iodo; Cyanic acid;-XR 6, wherein X be oxygen ,-S (O) n-or-NR 7-, wherein n is 0,1 or 2, R 6Be selected from by following each group of forming of base: alkyl, through substituted alkyl, aryl, through substituted aryl, heteroaryl, through substituted heteroaryl, heterocycle with through substituted heterocycle, and R 7Be hydrogen, alkyl or aryl, restricted condition is:
A) work as R 2For when the substituted alkyl, said substituting group does not comprise trifluoromethyl;
B)-XR 6It is not alkoxyl group; And
C) as-XR 6For when the substituted alkoxy, said substituting group does not comprise benzyl or through being selected from by (C 1-C 5) alkyl and (C 1-C 5) group that forms of alkoxyl group the substituted benzyl of substituting group or do not comprise the Fluoroalkyloxy substituting group of following formula:
-O-[CH 2] x-C fH (2f+1-g)F g
Wherein x is 0 or 1; F is 1 to 5 integer; And g is 1 integer to (2f+1); Or
3) R 3For through substituted alkyl; Aryl; Through substituted aryl; Heteroaryl; Through substituted heteroaryl; Bromo; Iodo;-XR 6, wherein X be oxygen ,-S (O) n-or-NR 7-, wherein n is 0,1 or 2, R 6Be selected from by following each group of forming of base: alkyl, through substituted alkyl, aryl, through substituted aryl, heteroaryl, through substituted heteroaryl, heterocycle with through substituted heterocycle, and R 7Be hydrogen, alkyl or aryl, restricted condition is:
A) work as R 3For when the substituted alkyl, said substituting group does not comprise trifluoromethyl;
B)-XR 6It is not alkoxyl group; And
C) as-XR 6For when the substituted alkoxy, said substituting group does not comprise benzyl or via being selected from (C 1-C 5) alkyl and (C 1-C 5) group that forms of alkoxyl group the substituted benzyl of substituting group or do not comprise the Fluoroalkyloxy substituting group of following formula:
-O-[CH 2] x-C fH (2f+1-g)F g
Wherein x is 0 or 1; F is 1 to 5 integer; And g is 1 integer to (2f+1); Or
4) R 4Be iodo; Through substituted alkyl; Aryl; Through substituted aryl; Heteroaryl; Through substituted heteroaryl;-XR 6, wherein X be oxygen ,-S (O) n-or-NR 7-, wherein n is 0,1 or 2, R 6Be selected from by following each group of forming of base: alkyl, through substituted alkyl, aryl, through substituted aryl, heteroaryl, through substituted heteroaryl, heterocycle with through substituted heterocycle, and R 7Be hydrogen, alkyl or aryl, restricted condition is:
A) work as R 4For when the substituted alkyl, said substituting group does not comprise trifluoromethyl;
B)-XR 6It is not alkoxyl group; And
C) as-XR 6For when the substituted alkoxy, said substituting group does not comprise the Fluoroalkyloxy substituting group of following formula:
-O-[CH 2] x-C fH (2f+1-g)F g
Wherein x is 0 or 1; F is 1 to 5 integer; And g is 1 integer to (2f+1); Or
5) R 5Be iodo; Through substituted alkyl; Aryl; Through substituted aryl; Heteroaryl; Through substituted heteroaryl;-XR 6, wherein X be oxygen ,-S (O) n-or-NR 7-, wherein n is 0,1 or 2, R 6Be selected from by following each group of forming of base: alkyl, through substituted alkyl, aryl, through substituted aryl, heteroaryl, through substituted heteroaryl, heterocycle with through substituted heterocycle, and R 7Be hydrogen, alkyl or aryl, restricted condition is:
A) work as R 5For when the substituted alkyl, said substituting group does not comprise trifluoromethyl;
B)-XR 6It is not alkoxyl group; And
C) as-XR 6For when the substituted alkoxy, said substituting group does not comprise the Fluoroalkyloxy substituting group of following formula:
-O-[CH 2] x-C fH (2f+1-g)F g
Wherein x is 0 or 1; F is 1 to 5 integer; And g is 1 integer to (2f+1);
And further have following restricted condition:
Work as R 1, R 3, R 4And R 5During for hydrogen, R 2It is not bromo.
In an alternate embodiment, the compound of formula I is represented by formula IA:
Figure BDA00001645958400081
R wherein 1, R 2, R 3, R 4, R 5, R, R ', R ", R ' " as above define with q; And pharmaceutically acceptable salt, ester, prodrug.
In another alternate embodiment, the compound of formula I is represented by formula IB:
Figure BDA00001645958400082
R wherein 1, R 2, R 3, R 4, R 5, R ", R ' ", WR 8As above define with q; And pharmaceutically acceptable salt, ester, prodrug.
In another alternate embodiment, the present invention is directed to the compound of representing by formula IC:
Figure BDA00001645958400091
R wherein 1, R 2, R 3, R 4, R 5, R, R ', R ", R ' ", WR 8As above define with q; And pharmaceutically acceptable salt, ester, prodrug.
In another alternate embodiment, the present invention is directed to the compound of representing by formula ID:
Figure BDA00001645958400092
R wherein 1, R 2, R 3, R 4, R 5, R, R ', R ", R ' " as above define with q; And pharmaceutically acceptable salt, ester, prodrug.
In other embodiments, the present invention is directed to the compound of representing by formula IIA, IIB, IIC and IID, wherein said formula such as hereinafter definition.
Preferred embodiment
In the compound of formula I, IA, IB, IC and ID, R 1Preferable being selected from by following each group of forming of base: hydrogen, alkyl, through substituted alkyl, halogen, alkoxyl group, aryloxy, through substituted aryloxy, through substituted aryl, alkylthio, aminoacyl, aryl, through substituted-amino, heteroaryl, heteroaryloxy ,-S (O) n-aryl, warp-S (O) n-substituted aryl ,-S (O) n-heteroaryl and warp-S (O) n-substituted heteroaryl, wherein n is 0,1 or 2.
R 1The better group that forms by following each base that is selected from:
(3-p-methoxy-phenyl) sulfenyl;
(4-chloro-phenyl-) sulfenyl;
(4-aminomethyl phenyl) sulfenyl;
The 2-fluorophenoxy;
2-methoxyl group phenoxy;
(2-p-methoxy-phenyl) sulfenyl;
The 3-fluorophenoxy;
3-methoxyl group phenoxy;
4-(methyl carbonylamino) phenoxy;
4-(methyl sulfonamido) phenoxy;
The 4-fluorophenoxy;
4-methoxyl group phenoxy;
4-p-methoxy-phenyl sulfenyl;
The 4-aminomethyl phenyl;
Bromo;
Chloro;
Dimethylamino methyl;
Oxyethyl group;
The ethyl sulfenyl;
Hydrogen;
Sec.-propyl;
Methoxyl group;
Methoxymethyl;
Methyl;
N, N-dimethylamino carbonyl;
Naphthalene-2-base oxygen base;
The naphthyl sulfenyl;
Phenoxy;
Phenyl;
Phenylamino;
The phenyl sulfinyl;
The phenyl sulfenyl;
Pyridine-2-base oxygen base;
Pyridine-2-base; With
Pyridine-2-base sulfenyl.
In the compound of formula I, IA, IB, IC and ID, R 2Preferable being selected from by following each group of forming of base: through substituted-amino, aryloxy, through substituted aryloxy, alkoxyl group, through substituted alkoxy, halogen, hydrogen, alkyl, through substituted alkyl, aryl ,-S (O) n-aryl, warp-S (O) n-substituted aryl ,-S (O) n-naphthenic base, wherein n is 0,1 or 2, aminocarbonyl amino, heteroaryloxy and cycloalkyloxy.
R 2The better group that forms by following each base that is selected from:
(4-methoxyl group) phenyl sulfonyl amino;
2, the 6-dimethyl phenoxy;
3,4-two fluorophenoxies;
3,5-two fluorophenoxies;
3-chloro-4-fluorophenoxy;
3-methoxyl group-4-fluorophenoxy;
3-methoxyl group-5-fluorophenoxy;
4-(methyl sulfonamido) phenoxy;
4-(phenyl sulfonamido) phenoxy;
4-CF 3-O-phenoxy;
4-CF 3-phenoxy;
The 4-chlorophenoxy;
The 4-fluorophenoxy;
4-(4-fluorophenoxy) phenoxy;
4-methoxyl group phenoxy;
4-nitrophenoxy;
Benzyloxy;
Bromo;
Butoxy;
CF 3；
Chloro;
Cyclohexyloxy;
The hexamethylene sulfenyl;
The cyclohexyl alkylsulfonyl;
Fluorine-based;
Hydrogen;
Iodo;
Isopropoxy;
Methyl;
Phenoxy;
Phenyl;
The phenyl sulfenyl;
The phenyl sulfinyl;
Benzenesulfonyl;
Phenylurea;
Pyridine-1-base sulfenyl;
Pyridin-3-yl oxygen base; With
The pyridin-4-yl sulfenyl.
In the compound of formula I, IA, IB, IC and ID, R 3Preferable being selected from by following each group of forming of base: through substituted aryloxy, through substituted alkoxy, alkoxyl group, through substituted alkyl, alkyl, amino, cycloalkyloxy, hydrogen, halogen, aryl ,-S (O) n-aryl, warp-S (O) n-substituted aryl ,-S (O) n-heteroaryl and warp-S (O) n-substituted heteroaryl, wherein n is 0,1 or 2, aminocarbonyl amino and heteroaryloxy.
R 3The better group that forms by following each base that is selected from:
Amino;
(4-methyl) benzene fulfonic amide phenoxyl;
3,4-two fluorophenoxies;
3,5-two fluorophenoxies;
3-fluoro-5-methoxyl group-phenoxy;
3-chloro-4-fluorophenoxy;
4-CF 3-O-phenoxy;
4-CF 3-phenoxy;
The 4-chlorophenoxy;
The 4-fluorophenoxy;
4-(4-fluorophenoxy) phenoxy;
4-methoxyl group phenoxy;
Benzyloxy;
Bromo;
Butoxy;
CF 3；
Chloro;
Cyclohexyloxy;
Hydrogen;
Iodo;
Isopropoxy;
Phenoxy;
Phenyl;
The phenyl sulfenyl;
Benzenesulfonyl;
The phenyl sulfinyl;
Phenylurea;
Pyridine-1-base sulfenyl;
Pyridin-3-yl oxygen base; With
The pyridin-4-yl sulfenyl.
Perhaps, R 2And R 3With side joint carbon atom combination on it, and be connected to form aryl.Said aryl is preferably phenyl.
In the compound of formula I, IA, IB, IC and ID, R 4Preferable being selected from: through replacement arylthio, halogen, hydrogen, through substituted alkyl and aryl by following each group of forming of base.
R 4The better group that forms by following each base that is selected from:
(4-chloro-phenyl-) sulfenyl;
Chloro;
Hydrogen;
Methoxymethyl; With
Phenyl;
In the compound of formula I, IA, IB, IC and ID, R 5Be preferably hydrogen or aryl.R 5Be more preferred from hydrogen or phenyl.
In the compound of formula I, IA and IC, the preferable group that forms by hydrogen, deuterium, aryl and alkyl that is selected from of R.The better group that forms by phenyl, hydrogen, deuterium and methyl that is selected from of R.
In the compound of formula I, IA and IC, R ' is selected from preferable by hydrogen, deuterium, alkyl, through substituted alkyl and the group that forms through substituted-amino.The better group that forms by following each base that is selected from of R ':
The amino butyl of 4-;
The 4-hydroxybenzyl;
Benzyl;
Ethyloic;
Deuterium;
Methylol;
The imidazol-4 yl methyl;
Sec.-propyl;
Methyl; With
Propyl group.
Perhaps, R and R ' are connected to form naphthenic base with side joint carbon atom on it, are more preferred from cyclopropyl.
In the compound of formula I, IA and IC, R " is preferably hydrogen, alkyl or through substituted alkyl." better be hydrogen, methyl or ethyloic (CH to R 2C (O) OH).Perhaps, " and side joint carbon atom and nitrogen-atoms on it is connected to form heterocyclic radical respectively, is more preferred from pyrrolidyl for R ', R.
In the compound of formula I, IA, IB, IC and ID, R ' " preferable group that forms by following each base that is selected from: hydrogen, hydroxyl, alkoxyl group, through substituted alkoxy, cycloalkyloxy, through substituted cyclo alkoxy, thiol, acyloxy and aryl.R ' " the preferable group that forms by following each base that is selected from:
Hydroxyl;
Benzyloxy;
Oxyethyl group;
Thiol;
Methoxyl group;
Methyl ketonic oxygen base; With
Phenyl.
In the compound of formula I, IB and IC, WR 8Preferable be selected from by amino, through group that substituted-amino, aminoacyl, hydroxyl and alkoxyl group are formed.WR 8The better group that forms by following each base that is selected from:
Amino;
Dimethylamino;
Hydroxyl;
Methoxyl group; With
The methyl carbonylamino.
The representative compound that is used for said application is shown in Table A-D, and is wherein alphabetical corresponding to letter (that is, the representative compound of formula IA is in Table A) in the structural formula in the form.
Table A
Figure BDA00001645958400151
Sequence number R 1 R 2 R 3 R R′ R"
1 Cl H Benzyloxy H Methyl H
2 Cl H H H Methylol H
3 Cl H H H Methylol H
4 Cl H Isopropoxy H Methylol H
5 Cl H Isopropoxy H Methylol H
6 Cl Isopropoxy H H Methylol H
7 Cl Isopropoxy H H Methylol H
8 Cl H H Methyl Methyl H
9 Cl H Isopropoxy Methyl Methyl H
10 Cl H H H The imidazol-4 yl methyl H
11 Cl H H H The imidazol-4 yl methyl H
12 Cl H H H Sec.-propyl H
13 Cl H H H Sec.-propyl H
14 Cl H Isopropoxy H Sec.-propyl H
Figure BDA00001645958400152
Figure BDA00001645958400161
Figure BDA00001645958400171
Table B
Sequence number R 2 R 3 WR 8
1 H H Methoxyl group
2 Isopropoxy H Amino
3 H Isopropoxy Methoxyl group
4 H H Amino
5 H H Hydroxyl
6 H Isopropoxy Hydroxyl
7 H H Dimethylamino
8 H H The methyl carbonylamino
9 H Isopropoxy Amino
10 H Isopropoxy Dimethylamino
11 Isopropoxy H Methoxyl group
12 Isopropoxy H Dimethylamino
13 Isopropoxy H Hydroxyl
Table C
Sequence number R 2 R 3
1 Isopropoxy H
2 H Isopropoxy
3 H H
Table D
Figure BDA00001645958400191
Figure BDA00001645958400192
Figure BDA00001645958400202
Figure BDA00001645958400211
Figure BDA00001645958400212
Figure BDA00001645958400221
Figure BDA00001645958400222
Figure BDA00001645958400231
Figure BDA00001645958400242
The compound that is included in the category of the present invention comprises, for example following compound of stating:
{ [4-hydroxyl-1-(naphthalene-2-base oxygen base)-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
{ [4-hydroxyl-1-(pyridin-3-yl oxygen base)-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
{ [4-hydroxyl-1-(4-methoxyl group-phenoxy)-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
{ [4-hydroxyl-1-(3-methoxyl group-phenoxy)-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
{ [1-(3-fluoro-phenoxy)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
{ [1-(4-fluoro-phenoxy)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
{ [1-(2-fluoro-phenoxy)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
{ [4-hydroxyl-1-(2-methoxyl group-phenoxy)-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
{ [1-(4-acetylaminohydroxyphenylarsonic acid phenoxy)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
{ [4-hydroxyl-1-(4-methanesulfonamido-phenoxy)-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
[(4-hydroxyl-1-phenyl amino-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
{ [4-hydroxyl-6-(pyridin-3-yl oxygen base)-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
{ [4-hydroxyl-7-(pyridin-3-yl oxygen base)-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
[(1-chloro-4-methoxyl group-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(1-chloro-4-oxyethyl group-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(4-hydroxyl-1-methoxyl group-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(1-oxyethyl group-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(4-acetoxyl group-1-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(4-hydroxyl-1-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(1-oxyethyl group-4-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(1-chloro-4-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(4-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(4-hydroxyl-1-methyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(4-hydroxyl-1-methoxymethyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(1-dimethylamino formyl radical-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(4-hydroxyl-1-methyl-6-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(4-hydroxyl-1-methyl-7-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(4-benzyloxy-1-methyl-7-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(4-oxyethyl group-1-methyl-7-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(1-dimethylamino formyl radical-4-hydroxyl-7-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(4-hydroxyl-1-methoxymethyl-7-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(4-hydroxyl-1-p-methylphenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
{ [7-(4-fluoro-phenoxy)-4-hydroxyl-1-methyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
{ [1-chloro-4-hydroxyl-7-(4-methoxyl group-phenoxy)-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
{ [4-hydroxyl-7-(4-methoxyl group-phenoxy)-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
{ [1-chloro-4-hydroxyl-6-(4-methoxyl group-phenoxy)-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
{ [4-hydroxyl-6-(4-methoxyl group-phenoxy)-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
{ [1-chloro-4-hydroxyl-7-(4-trifluoromethyl-phenoxy)-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
{ [4-hydroxyl-7-(4-trifluoromethyl-phenoxy)-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
{ [1-chloro-4-hydroxyl-6-(4-trifluoromethyl-phenoxy)-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
{ [4-hydroxyl-6-(4-trifluoromethyl-phenoxy)-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
{ [1-chloro-7-(4-fluoro-phenoxy)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
{ [7-(4-fluoro-phenoxy)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
{ [1-chloro-6-(4-fluoro-phenoxy)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
{ [6-(4-fluoro-phenoxy)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
{ [4-hydroxyl-7-(pyridin-4-yl sulfenyl)-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
{ [4-hydroxyl-6-(pyridin-4-yl sulfenyl)-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
[(7-benzenesulfinyl-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(7-benzenesulfonyl-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(6-benzenesulfinyl-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(6-benzenesulfonyl-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(6-amino-4-hydroxy-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
{ [4-hydroxyl-7-(4-methoxyl group-phenylsulfonamido)-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
{ [4-hydroxyl-7-(3-phenyl-urea groups)-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
{ [4-hydroxyl-6-(3-phenyl-urea groups)-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
{ [4-hydroxyl-1-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
{ [1-(4-chloro-phenyl sulfenyl)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
[(4-hydroxyl-1-p-methylphenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
{ [4-hydroxyl-1-(pyridine-2-base sulfenyl)-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
{ [4-hydroxyl-1-(3-methoxyl group-phenyl sulfenyl)-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
{ [4-hydroxyl-1-(2-methoxyl group-phenyl sulfenyl)-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
{ [4-hydroxyl-1-(naphthalene-2-base sulfenyl)-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
[(1-benzenesulfinyl-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(1-benzenesulfonyl-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
{ [4-hydroxyl-7-(pyridine-2-base sulfenyl)-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
{ [4-hydroxyl-6-(pyridine-2-base sulfenyl)-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
[(1-chloro-4-hydroxyl-6,7-two phenoxys-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(4-hydroxyl-6,7-two phenoxys-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
({ 4-hydroxyl-7-[4-(toluene-4-sulfonamido)-phenoxy]-isoquinoline 99.9-3-carbonyl }-amino)-acetate;
{ [4-hydroxyl-7-(4-nitro-phenoxy)-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
[(4-sulfydryl-7-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(4-sulfydryl-7-trifluoromethyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
{ [7-(4-phenylsulfonamido-phenoxy)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
{ [4-hydroxyl-7-(4-methanesulfonamido-phenoxy)-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
{ [7-(4-chloro-phenoxy)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
{ [6-(4-chloro-phenoxy)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
{ [6-(3-fluoro-5-methoxyl group-phenoxy)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
{ [7-(3-fluoro-5-methoxyl group-phenoxy)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
{ [7-(3,4-two fluoro-phenoxys)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
{ [6-(3,4-two fluoro-phenoxys)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
{ [4-hydroxyl-7-(4-trifluoromethoxy-phenoxy)-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
{ [4-hydroxyl-6-(4-trifluoromethoxy-phenoxy)-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
2-(S)-{ [7-(4-chloro-phenoxy)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-propionic acid;
2-(S)-{ [6-(4-chloro-phenoxy)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-propionic acid;
2-{ [7-(3,4-two fluoro-phenoxys)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-propionic acid;
2-(S)-[(4-hydroxyl-7-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid;
2-(R)-[(4-hydroxyl-7-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid;
2-(R)-[(4-hydroxyl-7-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid;
2-(S)-{ [4-hydroxyl-7-(4-methoxyl group-phenoxy)-isoquinoline 99.9-3-carbonyl]-amino }-propionic acid;
2-(S)-[(7-benzenesulfonyl-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid;
(R)-2-[(4-hydroxyl-1-methoxymethyl-7-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid;
(S)-2-[(4-hydroxyl-1-methoxymethyl-7-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid;
(S)-2-[(4-sulfydryl-7-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid;
(S)-2-{ [1-(4-chloro-phenyl sulfenyl)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-propionic acid;
(R)-2-{ [1-(4-chloro-phenyl sulfenyl)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-propionic acid;
[(4-hydroxyl-7-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(4-hydroxyl-6-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(1-chloro-4-hydroxyl-7-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(1-chloro-4-hydroxyl-6-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(1-bromo-4-hydroxyl-7-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(1-bromo-4-hydroxyl-6-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(4-hydroxyl-7-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(4-hydroxyl-6-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(1-chloro-4-hydroxyl-7-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(1-chloro-4-hydroxyl-6-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(1-bromo-4-hydroxyl-7-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(1-bromo-4-hydroxyl-6-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
{ [7-(2,6-dimethyl--phenoxy)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
{ [1-chloro-7-(2,6-dimethyl--phenoxy)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
{ [1-bromo-7-(2,6-dimethyl--phenoxy)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
[(1-bromo-7-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(1-bromo-6-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(1-bromo-4-hydroxyl-7-trifluoromethyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(1-bromo-4-hydroxyl-6-trifluoromethyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(4-hydroxyl-1-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(1,7-two bromo-4-hydroxyl-isoquinoline 99.9-3-carbonyls)-amino]-acetate;
[(7-bromo-1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(6-bromo-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(1-bromo-7-fluoro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(7-fluoro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(1-chloro-7-fluoro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(1-chloro-4-hydroxyl-benzo [g] isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(1-bromo-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(4-hydroxyl-6-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(4-hydroxyl-7-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(1-chloro-4-hydroxyl-6-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(1-chloro-4-hydroxyl-7-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(1-bromo-4-hydroxyl-6-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(1-bromo-4-hydroxyl-7-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(4-hydroxyl-5-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(4-hydroxyl-8-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(1-chloro-4-hydroxyl-5-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(1-chloro-4-hydroxyl-8-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(1-bromo-4-hydroxyl-5-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(1-bromo-4-hydroxyl-8-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(1-ethyl sulfenyl-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
{ [4-hydroxyl-1-(4-methoxyl group-phenyl sulfenyl)-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
[(1-chloro-4-hydroxyl-7-iodo-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(1-chloro-4-hydroxyl-6-iodo-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(4-hydroxyl-7-iodo-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(1-bromo-4-hydroxyl-7-methyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(1-bromo-7-butoxy-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(1-bromo-6-butoxy-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(6-benzyloxy-1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-methyl-amino]-acetate;
[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-methyl-amino]-acetate;
[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-methyl-amino]-acetate;
[(1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline 99.9-3-carbonyl)-methyl-amino]-acetate;
[ethyloic-(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[ethyloic-(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid (2-amino-ethyl)-acid amides (three fluoro-acetates);
1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid (2-methoxyl group-ethyl)-acid amides;
1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid (2-hydroxyl-ethyl)-acid amides;
1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid (2-dimethylamino-ethyl)-acid amides;
1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid (2-acetylaminohydroxyphenylarsonic acid ethyl)-acid amides;
1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline-3-carboxylic acid (2-hydroxyl-ethyl)-acid amides;
1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline-3-carboxylic acid (2-methoxyl group-ethyl)-acid amides;
1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline-3-carboxylic acid (2-amino-ethyl)-acid amides (three fluoro-acetates);
1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline-3-carboxylic acid (2-dimethylamino-ethyl)-acid amides;
1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline-3-carboxylic acid (2-amino-ethyl)-acid amides (three fluoro-acetates);
1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline-3-carboxylic acid (2-methoxyl group-ethyl)-acid amides;
1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline-3-carboxylic acid (2-dimethylamino-ethyl)-acid amides;
1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline-3-carboxylic acid (2-hydroxyl-ethyl)-acid amides;
(S)-2-[(6-benzyloxy-1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid;
(R)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-3-hydroxyl-propionic acid;
(S)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-3-hydroxyl-propionic acid;
(R)-2-[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-3-hydroxyl-propionic acid;
(S)-2-[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-3-hydroxyl-propionic acid;
(R)-2-[(1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-3-hydroxyl-propionic acid;
(S)-2-[(1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-3-hydroxyl-propionic acid;
2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-2-methyl-propionic acid;
2-[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-2-methyl-propionic acid;
(R)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-3-(lH-imidazol-4 yl)-propionic acid (three fluoro-acetates);
(S)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-3-(lH-imidazol-4 yl)-propionic acid (three fluoro-acetates);
(R)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-3-methyl-butyric acid;
(S)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-3-methyl-butyric acid;
(R)-2-[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-3-methyl-butyric acid;
(S)-2-[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-3-methyl-butyric acid;
(R)-2-[(1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-3-methyl-butyric acid;
(S)-2-[(1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-3-methyl-butyric acid;
(S)-2-[(6-benzyloxy-1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-3-methyl-butyric acid;
(R)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-3-phenyl-propionic acid;
(S)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-3-phenyl-propionic acid;
(R)-2-[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-3-phenyl-propionic acid;
(S)-2-[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-3-phenyl-propionic acid;
(R)-2-[(1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-3-phenyl-propionic acid;
(S)-2-[(1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-3-phenyl-propionic acid;
(R)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-3-(4-hydroxyl-phenyl)-propionic acid;
(S)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-3-(4-hydroxyl-phenyl)-propionic acid;
(R)-2-[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-3-(4-hydroxyl-phenyl)-propionic acid;
(S)-2-[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-3-(4-hydroxyl-phenyl)-propionic acid;
(R)-2-[(1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-3-(4-hydroxyl-phenyl)-propionic acid;
(S)-2-[(1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-3-(4-hydroxyl-phenyl)-propionic acid;
(R)-2-[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-valeric acid;
(S)-2-[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-valeric acid;
(R)-1-(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-tetramethyleneimine-2-formic acid;
(S)-1-(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-tetramethyleneimine-2-formic acid;
(R)-1-(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-tetramethyleneimine-2-formic acid;
(S)-1-(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-tetramethyleneimine-2-formic acid;
(R)-6-amino-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-caproic acid (three fluoro-acetates);
(S)-6-amino-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-caproic acid (three fluoro-acetates);
(R)-6-amino-2-[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-caproic acid; Trifluoroacetate;
(S)-6-amino-2-[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-caproic acid (three fluoro-acetates);
(R)-6-amino-2-[(1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-caproic acid; Trifluoroacetate;
(S)-6-amino-2-[(1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-caproic acid (three fluoro-acetates);
(R)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-succsinic acid;
(S)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-succsinic acid;
(R)-2-[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-succsinic acid;
(S)-2-[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-succsinic acid;
(R)-2-[(1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-succsinic acid;
1-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-cyclopropanecarboxylic acid;
1-[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-cyclopropanecarboxylic acid;
Two deuteriums-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
(R)-2-[(6-benzyloxy-1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid;
(S)-2-[(7-benzyloxy-1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid;
(R)-2-[(7-benzyloxy-1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid;
(S)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid;
(R)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid;
(S)-2-[(6-isopropoxy-1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid;
(R)-2-[(6-isopropoxy-1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid;
(S)-2-[(7-isopropoxy-1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid;
(R)-2-[(7-isopropoxy-1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid;
1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline-3-carboxylic acid (2-hydroxyl-1-methylol-ethyl)-acid amides;
1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline-3-carboxylic acid (2-hydroxyl-1-methylol-ethyl)-acid amides;
1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid (2-hydroxyl-1-methylol-ethyl)-acid amides;
{ [7-(3,5-two fluoro-phenoxys)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
{ [6-(3,5-two fluoro-phenoxys)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
({ 7-[4-(4-fluoro-phenoxy)-phenoxy]-4-hydroxyl-isoquinoline 99.9-3-carbonyl }-amino)-acetate;
({ 6-[4-(4-fluoro-phenoxy)-phenoxy]-4-hydroxyl-isoquinoline 99.9-3-carbonyl }-amino)-acetate;
{ [7-(3-chloro-4-fluoro-phenoxy)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
{ [6-(3-chloro-4-fluoro-phenoxy)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
(S)-2-{ [7-(3-fluoro-5-methoxyl group-phenoxy)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-propionic acid;
2-(S)-[(7-cyclohexyloxy-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid;
2-(S)-{ [7-(4-fluoro-phenoxy)-4-hydroxyl-1-methyl-isoquinoline 99.9-3-carbonyl]-amino }-propionic acid;
2-(S)-{ [7-(4-fluoro-phenoxy)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-propionic acid;
2-(S)-[(4-hydroxyl-1-methyl-7-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid;
2-(S)-[(4-hydroxyl-1-methyl-7-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid;
2-(S)-{ [4-hydroxyl-7-(4-trifluoromethyl-phenoxy)-isoquinoline 99.9-3-carbonyl]-amino }-propionic acid;
{ [7-(4-chloro-phenoxy)-4-hydroxyl-1-methyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
{ [6-(4-chloro-phenoxy)-4-hydroxyl-1-methyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
{ [7-(3,5-two fluoro-phenoxys)-4-hydroxyl-1-methyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
{ [4-hydroxyl-7-(4-methoxyl group-phenoxy)-1-methyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
{ [4-hydroxyl-6-(4-methoxyl group-phenoxy)-1-methyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
[(6-cyclohexyloxy-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(7-cyclohexyloxy-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(7-cyclohexyloxy-4-hydroxyl-1-methyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(7-hexamethylene sulfenyl-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(7-hexamethylene alkylsulfonyl-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(4-hydroxyl-1-isobutyl--isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(4-hydroxyl-1-pyridine-2-base-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(1-ethyl-4-hydroxyl-7-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(1-dimethylamino methyl-4-hydroxyl-7-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(4-hydroxyl-1-methyl-7-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
{ [4-hydroxyl-1-methyl-7-(4-trifluoromethyl-phenoxy)-isoquinoline 99.9-3-carbonyl]-amino }-acetate; With
Its pharmaceutically acceptable salt, ester and prodrug.
In another embodiment of the present invention, a kind of medical composition is provided, it comprises a kind of pharmaceutically acceptable vehicle or supporting agent and a kind of formula I compound of significant quantity or mixture of said compound of treating.
Also provide a kind of treatment, prevention or treatment in advance at least part by the method for the patient's condition of HIF and/or EPO mediation.Said method comprises throws the compound with formula I structure that gives mammal patient treatment significant quantity, and restricted condition is that said compound is not selected from the group that is made up of following material:
N-((1-chloro-4-hydroxyl-7-(2-propoxy-) isoquinoline 99.9-3-yl)-carbonyl)-glycocoll,
N-((1-chloro-4-hydroxyl-6-(2-propoxy-) isoquinoline 99.9-3-yl)-carbonyl)-glycocoll,
N-((1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino)-acetate,
N-((1-chloro-4-hydroxyl-7-methoxyl group isoquinoline 99.9-3-yl)-carbonyl)-glycocoll,
N-((1-chloro-4-hydroxyl-6-methoxyl group isoquinoline 99.9-3-yl)-carbonyl)-glycocoll,
N-((7-butoxy-1-chloro-4-hydroxyl isoquinoline 99.9-3-yl)-carbonyl)-glycocoll,
N-((6-benzyloxy-1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino)-acetate,
N-((7-benzyloxy-1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino)-acetate,
N-((8-chloro-4-hydroxyl isoquinoline 99.9-3-yl)-carbonyl)-glycocoll,
N-((7-butoxy-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino)-acetate and
((7-benzyloxy-1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino) methyl acetate.
Another embodiment of the present invention provides a kind of inhibition to be used to regulate the method for the hydroxylase activity of hypoxia inducible factor alpha subunit.
A kind of compsn is also contained in the present invention, and it comprises formula I compound or formula I compound and at least a other the mixture of therapeutical agent combination.Said other therapeutical agent is preferably erythropoietin.
Description of drawings
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Before describing the present invention and method, should be appreciated that the present invention is not limited to described particular methodology, rules, clone, analysis and reagent, because these may change.Should be appreciated that also term used herein is in order to describing specific embodiment of the present invention, and by no means in order to be limited in the category of the present invention of stating in the accessory claim book.
Must be noted that, only if context has clearly indication in addition, otherwise in the literary composition with the accessory claim book in employed singulative " " and " said " comprise plural.
Only if definition is arranged in addition, all technology of using among this paper are identical with the general implication of understanding of those skilled in the art in the invention with scientific terminology.Although in practice of the present invention or test, can use and similar or suitable any method and material described herein, describe preferred methods, equipment and material now.For describe with disclose can the open case of related use with the present invention in reported method, reagent and instrument, the open case of being quoted among all this paper is incorporated herein by reference in full.This paper should be interpreted as the present invention and have the right to make said disclosure in advance because of previous invention.
Only if indication is arranged in addition, chemistry, biological chemistry, molecular biology, cytobiology, genetics, immunology and the pharmacological method of the routine under practice of the present invention will be used in the technical field.Said technology is fully explained in document.(see, for example mark publishing company (Mack Publishing Co.) publish nineteen ninety by Gennaro, the 18th edition of editing of A.R. " the Lei Shi pharmacy is complete works of " (Remington ' s Pharmaceutical Sciences); The academic press (Academic Press, Inc.) publish by Colowick, " Enzymology method " that people such as S. edit (Methods In Enzymology); " Backwill Science Press " (Blackwell Scientific Publications) published in 1986 by D.M.Weir and C.C.Blackwell edit " experiment immunization handbook (Handbook of Experimental Immunology) I-IV rolls up; " press of cold spring harbor laboratory " (Cold Spring Harbor Laboratory Press) published in 1989 by Maniatis, " molecular cloning: laboratory manual " of the second edition that people such as T. edit (Molecular Cloning:A Laboratory Manual) I-III volume; John Wei Li father and son publishing company (John Wiley Sons) published in 1999 by Ausubel, the 4th edition " the fine works molecular biology experiment guide " that people such as F.M edit (Short Protocols in Molecular Biology); " Protocols in Molecular Biology: reinforcement laboratory study course " (the Molecular Biology Techniques:An Intensive Laboratory Course) that edit by people such as Ream that academic press 1998 publishes; The 2nd edition PCR that edits by Newton and Graham that Springer Verlag Publishing Group (Springer Verlag) 1997 publishes " biotechnology cross the threshold book series " (Introduction to Biotechniques Series).
Term used herein " anaemia " refers to cause oxygen level reduces in the blood any oxyphorase or red blood corpuscle unusual.Anaemia maybe be relevant with unusual generation, processing or the performance of red blood corpuscle and/or oxyphorase.The term anaemia refers to any minimizing with respect to normal blood content of erythrocyte number in the blood and/or content of hemoglobin.
Anaemia can be caused by the for example acute or patient's condition such as chronic renal disease, infection, inflammation, cancer, irradiation, toxin, mellitus and operation.Infection can be caused by for example virus, bacterium and/or parasite etc.Inflammation can by infect, the autoimmune illness for example rheumatoid arthritis etc. cause.Anaemia also maybe with lose blood relevantly, said losing blood can be caused by for example stomach ulcer, duodenal ulcer, hemorrhoid, cancer of the stomach or large bowel cancer, wound, damage, surgical procedure etc.Anaemia is further dialysed relevant with radiotherapy, chemotherapy and kidney.Anaemia is also relevant with the HIV infected patient of experience Zidovodine (zidovudine (zidovudine)) or the treatment of other RTI, and can in the cancer patients of experience chemotherapy (for example experiencing the cyclic chemical therapy that contains Platinol (cisplatin) or do not contain Platinol), take place.Aplastic anemia and osteomyelodysplasia syndromes are and the marrow failure diseases associated that it can cause red blood corpuscle to produce minimizing.On the other hand, anaemia can be caused by defective or unusual oxyphorase or red blood corpuscle, for example in the illness that comprises microcytic anemia, hypochromic anemia etc.Anaemia can be caused by iron transfer, processing and utilization imbalance, for example see SA etc.
Used term " illness ", " disease " and " patient's condition " have the exhaustive implication, and refer to any normal situation that departs from.
Term " the anaemia patient's condition " is with " the anaemia illness " refers to any patient's condition relevant with anaemia, disease or illness.Said illness includes, but is not limited to above cited illness.The anaemia illness further includes, but is not limited to aplastic anemia; Autoimmune hemolytic anemia; Bone marrow transplantation; Qiu-Shi two syndromes (Churg-Strauss syndrome); Diamond-Blackfan anemia (Diamond Blackfan anemia); Anemia Fanconi's (Fanconi ' s anemia); The expense ear is carried syndrome (Felty syndrome); Graft versus host disease; Hemopoietic stem cell suppresses; Hemolytic uremic syndrome; The development of bone marrow abnormal syndrome; Nocturnal paroxysmal hemoglobinuria; Osteomyelofibrosis; Pancytopenia; Pure red cell aplasia; Purpura,Henoch-Schonlein (purpura Schoenlein-Henoch); SA; Increasing property of initiating cell refractory anemia; Rheumatoid arthritis; Shu Wake Man syndromes (Shwachman syndrome); Drepanocytosis; Major thalaseemia; Minor thalassemia; Thrombopenic purpura etc.
Term " erythropoietin related conditions " is also referring to and the relevant any patient's condition of normal, the unusual or improper adjusting of being lower than of erythropoietin of comprising property.The erythropoietin related conditions comprises increases any patient's condition that EPO content can provide the treatment benefit.The erythropoietin content relevant with the said patient's condition can be measured for the measuring method that the technician accepted and utilized in said field through any.The erythropoietin related conditions comprises the anaemia patient's condition, and is for example described above.
The erythropoietin related conditions further comprises neuroscience illness and/or damage, comprises the case of apoplexy, wound, epilepsy, neurodegenerative disease and similar disease, and wherein erythropoietin can provide neuroprotective.The neurodegenerative disease that the present invention is contained comprises Alzheimer's (Alzheimer ' s disease), Parkinson's disease (Parkinson ' s disease), Huntington (Huntington ' s disease) and similar disease.
Term " erythropoietin " refers to any reorganization or spontaneous erythropoietin, comprises for example rHuEPO (gene pool (GenBank) registration number AAA52400; People such as Lin; (1985) " PNAS " 82:7580-7584}, EPOETIN rHuEPO (Amgen; Inc., oak city, California), ARANESP rHuEPO (Amgen), PROCRIT rHuEPO (Ortho Biotech Products; L.P., Raritan NJ) etc.
" HIF α " refers to the proteic alpha subunit of hypoxia inducible factor to term.HIF α can be any mankind or other mammalian proteins, or its segment, comprises human HIF-1-1 α (gene pool registration number Q16665), HIF-2 α (gene pool registration number AAB41495) and HIF-3 α (gene pool registration number AAD22668); Muridae HIF-1 α (gene pool registration number Q61221), HIF-2 α (gene pool registration number BAA20130 and AAB41496) and HIF-3 α (gene pool registration number AAC72734); Rat HIF-1 α (gene pool registration number CAA70701), HIF-2 α (gene pool registration number CAB96612) and HIF-3 α (gene pool registration number CAB96611); With ox HIF-1 α (gene pool registration number BAA78675).HIF α also can be any nonmammalian albumen or its segment; Comprise Xenopus laevis (Xenopus laevis) HIF-1 α (gene pool registration number CAB96628), fruit rope (Drosophila melanogaster) HIF-1 α (gene pool registration number JC4851) and chicken HIF-1 α (gene pool registration number BAA34234).HIF α gene order also can obtain through conventional clone technology, for example through the above-mentioned HIF α of all or part gene order being restored as probe and measuring the HIF α gene order in another species.
The segment of HIF α comprises at least one function of reservation HIF α or any segment of constitutional features.The segment of HIF α comprises, and is for example defined like lower area by human HIF-1-1 α: amino acid 401 to 603 (people such as Huang, above-mentioned), amino acid 531 to 575 (people such as Jiang; (1997) " journal of biological chemistry " (J Biol.Chem); 272:19253-19260}, amino acid 556 to 575 (people such as Tanimoto, above-mentioned), amino acid 557 to 571 (people such as Srinivas, (1999) " biological chemistry and biophysical research communication "; 260:557-561}; With amino acid 556 to 575 (Ivan and Kaelin, (2001) " science " (Science), 292:464-468).On the other hand, HIF α segment comprises any segment that contains at least one motif LXXLAP, for example occurs in L397TLLAP and L559EMLAP place in the human HIF-1-1 α natural sequence.
HIF α and its segmental term " aminoacid sequence " or " polypeptide that for example refers to that uses among this paper " is contained oligopeptides, peptide or protein sequence, or is referred to the segment of any of these material and refer to that nature exists or synthetic molecules." segment " can refer to keep any part of the sequence of proteic at least one structure or functional character.Causing immune segment or antigene fragment is polypeptide fragments, and being preferably length is about 5 to 15 amino acid whose segments, and it keeps at least a biology or immunologic competence.When " aminoacid sequence when having the peptide sequence of protein molecular " be used in reference to nature, " aminoacid sequence " and similar terms and do not mean that aminoacid sequence is limited to the whole natural sequences relevant with cited protein molecular.
" GAP-associated protein GAP " comprises other 2-oxoglutaric acid dioxygenase, especially likewise needs Fe the term that for example refers to HIF α prolyl hydroxylase GAP-associated protein GAP used herein 2+, 2-oxoglutaric acid and oxygen to be to keep the family member of hydroxylase activity.Said enzyme includes, but is not limited to, for example the factor of procollagen lysyl hydroxylase, procollagen prolyl 4-hydroxylase and inhibition HIF (FIH), the responsible mutual activatory l-asparagine of the HIF α acyl hydroxylase of regulating.(gene pool registration number AAL27308; People such as Mahon, (2001) " gene and growth " (Genes Dev), 15:2675-2686; People such as Lando, (2002) " science ", 295:858-861; With people such as Lando, (2002) " gene and growth ", 16:1466-1471.Also be shown in people such as Elkins, (2002) " journal of biological chemistry " (J Biol Chem) C200644200 etc.).
Term " HIF prolyl hydroxylase " and " HIF PH " be meant any can hydroxylation HIF albumen in the enzyme of proline residue.Through the preferable proline(Pro) of finding in the motif LXXLAP that comprises of the hydroxylated proline residue of HIF PH, for example come across L397TLLAP and L559EMLAP place in the human HIF-1-1 α natural sequence.HIF PH comprises by Taylor (2001; " gene " be 275:125-132 (Gene)) describe and by Aravind and Koonin (2001; " genome biology " (Genome Biol) 2:RESEARCH 0007); Egl-Nine (EGLN) the gene family member that people such as Epstein (2001, " cell " be 107:43-54 (Cell)) and Bruick and McKnight (2001, " science " 294:1337-1340) characterize.The instance of HIF PH enzyme comprises human SM-20 (EGLN1) (gene pool registration number AAG33965; People such as Dupuy (2000) " genomics " are 69:348-54 (Genomics)), EGLN2 isotype 1 (gene pool registration number CAC42510; Taylor, above-mentioned), EGLN2 isotype 2 (gene pool registration number NP_060025) and EGLN3 (gene pool registration number CAC42511; Taylor, above-mentioned); Mouse EGLN1 (gene pool registration number CAC42515), EGLN2 (gene pool registration number CAC42511) and EGLN3 (SM-20) (gene pool registration number CAC42517); With rat SM-20 (gene pool registration number AAA19321).In addition, HIF PH can comprise nematode (Caenorhabditis elegans) EGL-9 (gene pool registration number AAD56365) and drosophila melanogaster (Drosophila melanogaster) CG1114 gene product (gene pool registration number AAF52050).HIF PH also can comprise at least one structure of reservation of aforementioned full-length proteins or any segment of functional character.
Term " agonist " is meant a kind of molecule that increases or prolong the duration of effect of specific molecular.Agonist can comprise that protein, nucleic acid, glucide or any other increase the molecule of target molecule effect.
Term " antagonist " is meant a kind of biology or the degree of immunologic competence effect or molecule of time length that reduces specific molecular.Antagonist can comprise that protein, nucleic acid, glucide, antibody or any other reduce the molecule of target molecule effect.
Term " microarray " is meant any arrangement of nucleic acid, amino acid, antibody etc. on matrix.Matrix can be any proper supporting body, for example bead, glass, paper, soluble cotton, nylon or any suitable film etc.Matrix can be any rigidity or semi-rigid supporter, includes, but is not limited to film, strainer, wafer, chip, slide glass, fiber, bead (comprising magnetic or nonmagnetic bead), gel, tubing, culture plate, polymkeric substance, particulate, kapillary etc.Matrix can be provided for being coated with the surface and/or can have the kinds of surface form, for example wellhole, pin, groove, passage and pore make nucleic acid, amino acid etc. to combine with said matrix.
Term used herein " vehicle " is meant employed inertia or inactive substance in medicinal product or other tablet manufacturing, includes, but is not limited to any as tackiness agent, disintegrating agent, coating agent, compression/encapsulation auxiliary agent, newborn creme or lotion, lubricant, the non-enteron aisle material with agent, sweeting agent or spices, suspension/jelling agent or wet type granulating agent.Tackiness agent comprises for example carbopol (carbopol), Povidone, USP/EP, XG 550 etc.; The coating agent comprises, for example CELLULOSE ACETATE PHTHALATE, TKK 021, gelling gum (gellan gum), maltodextrin etc.; Compression/encapsulation auxiliary agent, for example lime carbonate, glucose, fructose dc, honey dc, lactose (anhydrous or monohydrate; According to circumstances with aspartame (aspartame), Mierocrystalline cellulose or Microcrystalline Cellulose combination), starch dc, sucrose etc.; Disintegrating agent comprises, for example Sodium Croscarmellose, gelling gum, carboxymethylstach sodium etc.; Breast creme or lotion comprise, for example maltodextrin, carrageenin etc.; Lubricant comprises, for example Magnesium Stearate, Triple Pressed Stearic Acid, sodium stearyl fumarate etc.; The material that is used for chewable tablet comprises, for example glucose, fructose dc, lactose (monohydrate; According to circumstances with aspartame or Mierocrystalline cellulose combination) etc.; Parenteral comprises with agent, for example N.F,USP MANNITOL, Povidone, USP/EP etc.; Softening agent comprises, for example Uniflex DBS, gather phthalic acid vinyl acetate etc.; Suspension/jelling agent comprises, for example carrageenin, carboxymethylstach sodium, XG 550 etc.; Sweeting agent comprises, for example aspartame, glucose, fructose dc, Sorbitol Powder, sucrose dc etc.; And the wet type granulating agent comprises, for example lime carbonate, maltodextrin, Microcrystalline Cellulose etc.
Term used herein " loading dose " is meant that initial throwing reaches the single or multiple doses of required pharmacology content rapidly.For example, the loading dose of relevant the inventive method refers to rapidly the for example plasma concns of The compounds of this invention increased to the initial dosage scheme of medicinal activity level.
Term used herein " inductive dose " is meant that initial throwing reaches the repeated doses intensity of required physiological responses rapidly.For example, the inductive dose of relevant the inventive method refers to rapidly hematocrit or hemoglobin level increased to the initial dosage scheme in the target zone, and said target zone can be normal plasma cell specific volume/hemoglobin level or is lower than this level.
Term used herein " maintenance dose " be meant the load or inductive dose after the throwing give in order to keep the dosage level of required physiological responses.For example, the maintenance dose of relevant the inventive method refers to hematocrit and/or oxyphorase are maintained the dosage in the required target zone, and said target zone can be normal plasma cell specific volume/hemoglobin level or is lower than this level.
Term used herein " sample " has wide significance.Sample can be from any source; For example, include, but is not limited to saliva, blood, urine, serum, blood plasma, vitreum, synovia, cerebrospinal fluid, amniotic fluid and organ-tissue (for example biological tissue) from body fluid, secretory product, tissue, cell or culturing cell; From karyomit(e), organoid or other film by cellular segregation; From genomic dna, cDNA, RNA, mRNA etc.; With from scavenger cell or tissue or from the trace or the marking of said cell or tissue.Sample also can be derived from any source, for example human experimenter or non-human mammal experimenter etc.Also contain the sample that is derived from any disease animal model.Sample can or can for example be fixed on the matrix or with it in solution and combine.Sample can refer to anyly be suitable for testing the material that erythropoietin or HIF α exist or refer to its segment, or any being suitable for screened any material of the molecule that increases erythropoietin or HIF α endogenous level or referred to its segment.The method that is used to obtain said sample is within the state of the art in said field.
Term used herein " experimenter " has wide significance.The experimenter can comprise protokaryon or eucaryon isolated cell, or cultivates the tissue of growing up.In certain embodiments, the experimenter is animal, particularly is selected from the animal of mammal, comprises rat, rabbit, Bovidae, sheep section, Suidae, Canidae, cat family, Muridae, equine and primates, and is particularly human.
" alkyl " used herein is meant the monovalent alkyl with 1 to 10 carbon atom, is preferably to have 1 to 5 carbon atom and be more preferred to have 1 to 3 carbon atom.The instance of this term is for example methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, the tertiary butyl, n-pentyl and similar group.
Be meant to have 1 to 5 substituting group through substituted alkyl; Preferable 1 to 3 substituent 1 to 10 carbon atom; The alkyl of preferable 1 to 5 carbon atom, it independently is selected from by following each group of forming of base: alkoxyl group, through substituted alkoxy, acyl group, amido, acyloxy, amino, through substituted-amino, aminoacyl, aminocarbonyl amino, amino thio-carbonyl-amino, aminocarbonyl oxygen base, aryl, through substituted aryl, aryloxy, through substituted aryloxy, aryloxy aryl, through substituted aryloxy aryl, cyanic acid, halogen, hydroxyl, nitro, oxo, sulfo-, carboxyl, carboxyl ester class, naphthenic base, through substituted cycloalkyl, thiol, alkylthio, through substituted alkane sulphur base, arylthio, through replace arylthio, cycloalkylthio, through replace cycloalkylthio, heteroarylthio, warp replacement heteroarylthio, heterocycle sulfenyl, through substituted heterocycle sulfenyl, heteroaryl, through substituted heteroaryl, heterocycle, through substituted heterocycle, cycloalkyloxy, through substituted cyclo alkoxy, heteroaryloxy, through substituted heteroaryloxy, heterocyclic oxy group, through substituted heterocyclyloxy, oxygen base carbonylamino, oxygen base thio-carbonyl-amino ,-OS (O) 2-alkyl ,-OS (O) 2-through substituted alkyl ,-OS (O) 2-aryl ,-OS (O) 2-through substituted aryl ,-OS (O) 2-heteroaryl ,-OS (O) 2-through substituted heteroaryl ,-OS (O) 2-heterocycle ,-OS (O) 2-through substituted heterocycle ,-OSO 2-NR 40R 40(each R wherein 40Be hydrogen or alkyl) ,-NR 40S (O) 2-alkyl ,-NR 40S (O) 2-through substituted alkyl ,-NR 40S (O) 2-aryl ,-NR 40S (O) 2-through substituted aryl ,-NR 40S (O) 2-heteroaryl ,-NR 40S (O) 2-through substituted heteroaryl ,-NR 40S (O) 2-heterocycle ,-NR 40S (O) 2-through substituted heterocycle ,-NR 40S (O) 2-NR 40-alkyl ,-NR 40S (O) 2-NR 40-through substituted alkyl ,-NR 40S (O) 2-NR 40-aryl ,-NR 40S (O) 2-NR 40-through substituted aryl ,-NR 40S (O) 2-NR 40-heteroaryl ,-NR 40S (O) 2-NR 40-through substituted heteroaryl ,-NR 40S (O) 2-NR 40-heterocycle and-NR 40S (O) 2-NR 40-through substituted heterocycle, each R wherein 40Be hydrogen or alkyl.
" alkoxyl group " refers to " alkyl-O-", and the example comprises methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, tert.-butoxy, sec.-butoxy, n-pentyloxy and similar group.
" through substituted alkoxy " refers to " through substituted alkyl-O-" base.
" acyl group " refer to H-C (O)-, alkyl-C (O)-, through substituted alkyl-C (O)-, thiazolinyl-C (O)-, through substituted alkenyl-C (O)-, alkynyl-C (O)-, through substituted alkynyl-C (O)-, naphthenic base-C (O)-, through substituted cycloalkyl-C (O)-, aryl-C (O)-, through substituted aryl-C (O)-, heteroaryl-C (O)-, through substituted heteroaryl-C (O), heterocycle-C (O)-and through substituted heterocycle-C (O)-; Restricted condition is heterocycle or do not combine with-C (O)-Ji through the nitrogen-atoms of substituted heterocycle, wherein alkyl, through substituted alkyl, thiazolinyl, through substituted alkenyl, alkynyl, through substituted alkynyl, naphthenic base, through substituted cycloalkyl, aryl, through substituted aryl, heteroaryl, through substituted heteroaryl, heterocycle and through substituted heterocycle in this paper definition.
The prefix of term " aminoacyl " or " carbamyl " or " carboxamide " or " through replacing carbamyl " or " through replacing carboxamide " refers to-C (O) NR 42R 42Base, wherein each R 42Independently be selected from by following each group of forming of base: hydrogen, alkyl, through substituted alkyl, thiazolinyl, through substituted alkenyl, alkynyl, through substituted alkynyl, aryl, through substituted aryl, naphthenic base, through substituted cycloalkyl, heteroaryl, through substituted heteroaryl, heterocycle, through substituted heterocycle and each R wherein 42Be connected with nitrogen-atoms to form heterocycle or through substituted heterocycle, wherein alkyl, through substituted alkyl, thiazolinyl, through substituted alkenyl, alkynyl, through substituted alkynyl, naphthenic base, through substituted cycloalkyl, aryl, through substituted aryl, heteroaryl, through substituted heteroaryl, heterocycle and through substituted heterocycle in this paper definition.
" acyloxy " refer to alkyl-C (O) O, through substituted alkyl-C (O) O-, thiazolinyl-C (O) O-, through substituted alkenyl-C (O) O-, alkynyl-C (O) O, through substituted alkynyl-C (O) O-, aryl-C (O) O-, through substituted aryl-C (O) O-, naphthenic base-C (O) O-, through substituted cycloalkyl-C (O) O-, heteroaryl-C (O) O-, through substituted heteroaryl-C (O) O-, heterocycle-C (O) O-with through substituted heterocycle-C (O) O-, wherein alkyl, through substituted alkyl, thiazolinyl, through substituted alkenyl, alkynyl, through substituted alkynyl, naphthenic base, through substituted cycloalkyl, aryl, through substituted aryl, heteroaryl, through substituted heteroaryl, heterocycle and through substituted heterocycle in this paper definition.
" thiazolinyl " refers to preferablely have 2 to 6 carbon atoms, and goodly has 2 to 4 carbon atoms and have at least 1, the thiazolinyl of preferable 1 to 2 unsaturated position of thiazolinyl.
" through substituted alkenyl " refers to have 1 to 3 substituting group and preferable 1 to 2 substituent thiazolinyl, and it is selected from by following each group of forming of base: alkoxyl group, through substituted alkoxy, acyl group, amido, acyloxy, amino, through substituted-amino, aminoacyl, aryl, through substituted aryl, aryloxy, through substituted aryloxy, cyanic acid, halogen, hydroxyl, nitro, carboxyl, carboxyl ester class, naphthenic base, through substituted cycloalkyl, heteroaryl, through substituted heteroaryl, heterocycle with through substituted heterocycle.
" alkynyl " refers to preferablely have 2 to 6 carbon atoms, and the better alkynyl that has 2 to 3 carbon atoms and have at least 1 and preferable 1 to-2 unsaturated position of alkynyl.
" through substituted alkynyl " refers to have 1 to 3 substituting group and preferable 1 to 3 substituent alkynyl, and it is selected from by following each group of forming of base: alkoxyl group, through substituted alkoxy, acyl group, amido, acyloxy, amino, through substituted-amino, aminoacyl, aryl, through substituted aryl, aryloxy, through substituted aryloxy, cyanic acid, halogen, hydroxyl, nitro, carboxyl, carboxyl ester class, naphthenic base, through substituted cycloalkyl, heteroaryl, through substituted heteroaryl, heterocycle with through substituted heterocycle.
" amino " refers to-NH 2Base.
" through substituted-amino " refers to-NR 41R 41Base, wherein each R 41Base independently is selected from by following each basic group that forms: hydrogen, alkyl, through substituted alkyl, thiazolinyl, through substituted alkenyl, alkynyl, through substituted alkynyl, naphthenic base, through substituted cycloalkyl, aryl, through substituted aryl, heteroaryl, through substituted heteroaryl, heterocycle, through substituted heterocycle ,-SO 2-alkyl ,-SO 2-through substituted alkyl ,-SO 2-thiazolinyl ,-SO 2-through substituted alkenyl ,-SO 2-naphthenic base ,-SO 2-through substituted cycloalkyl ,-SO 2-aryl ,-SO 2-through substituted aryl ,-SO 2-heteroaryl ,-SO 2-through substituted heteroaryl ,-SO 2-heterocycle ,-SO 2-through substituted heterocycle, restricted condition is R 41Base all is not a hydrogen; Or R 41Base can be connected with nitrogen-atoms with the formation heterocycle or through substituted heterocycle.
" amido " refers to-NR 45C (O) alkyl ,-NR 45C (O) through substituted alkyl ,-NR 45C (O) naphthenic base ,-NR 45C (O) through substituted cycloalkyl ,-NR 45C (O) thiazolinyl ,-NR 45C (O) through substituted alkenyl ,-NR 45C (O) alkynyl ,-NR 45C (O) through substituted alkynyl ,-NR 45C (O) aryl ,-NR 45C (O) through substituted aryl ,-NR 45C (O) heteroaryl ,-NR 45C (O) through substituted heteroaryl,
-NR 45C (O) heterocycle and-NR 45C (O) is through substituted heterocycle, wherein R 45Be hydrogen or alkyl and wherein alkyl, through substituted alkyl, thiazolinyl, through substituted alkenyl, alkynyl, through substituted alkynyl, naphthenic base, through substituted cycloalkyl, aryl, through substituted aryl, heteroaryl, through substituted heteroaryl, heterocycle and through substituted heterocycle in this paper definition.
" carbonyl oxygen base is amino " refers to-NR 46C (O) O-alkyl ,-NR 46C (O) O-through substituted alkyl ,-NR 46C (O) O-thiazolinyl ,-NR 46C (O) O-through substituted alkenyl ,-NR 46C (O) O-alkynyl ,-NR 46C (O) O-through substituted alkynyl ,-NR 46C (O) O-naphthenic base ,-NR 46C (O) O-through substituted cycloalkyl ,-NR 46C (O) O-aryl ,-NR 46C (O) O-through substituted aryl ,-NR 46C (O) O-heteroaryl ,-NR 46C (O) O-through substituted heteroaryl ,-NR 46C (O) O-heterocycle and-NR 46C (O) O-is through substituted heterocycle, wherein R 46Be hydrogen or alkyl and wherein alkyl, through substituted alkyl, thiazolinyl, through substituted alkenyl, alkynyl, through substituted alkynyl, naphthenic base, through substituted cycloalkyl, aryl, through substituted aryl, heteroaryl, through substituted heteroaryl, heterocycle and through substituted heterocycle in this paper definition.
The prefix of " aminocarbonyl oxygen base " or " carbamyl oxygen base " or " through replacing carbamyl oxygen base " refers to-OC (O) NR 47R 47Base, wherein each R 47Independent be hydrogen, alkyl, through substituted alkyl, thiazolinyl, through substituted alkenyl, alkynyl, through substituted alkynyl, naphthenic base, through substituted cycloalkyl, aryl, through substituted aryl, heteroaryl, through substituted heteroaryl, heterocycle with through substituted heterocycle or each R wherein 47Be connected with nitrogen-atoms forming heterocycle or through substituted heterocycle, and wherein alkyl, through substituted alkyl, thiazolinyl, through substituted alkenyl, alkynyl, through substituted alkynyl, naphthenic base, through substituted cycloalkyl, aryl, through substituted aryl, heteroaryl, through substituted heteroaryl, heterocycle and through substituted heterocycle in this paper definition.
" aminocarbonyl is amino " refers to-NR 49C (O) NR 49-Ji, wherein R 49Be to be selected from the group that forms by hydrogen and alkyl.
" aryl " or " virtue " refers to the monovalent aromatic carbocylic radical of 6 to 14 carbon atoms; It has monocycle (for example phenyl) or polynary condensed ring (for example naphthyl or anthryl); Said condensed ring can be or can be not for aromatic nucleus (for example; 2-benzoxazolinone, 2H-1,4-benzoxazine-3 (4H)-ketone-7-base and similar group thereof), restricted condition is that tie point is an aryl.Preferable phenyl and the naphthyl of comprising of aryl.
" through substituted aryl " refer to like the aryl that defines among this paper by 1 to 4, and preferable 1 to 3 is selected from substituting group of forming group by following each base and replaces: hydroxyl, acyl group, amido, carbonylamino sulfenyl, acyloxy, alkyl, through substituted alkyl, alkoxyl group, through substituted alkoxy, thiazolinyl, through substituted alkenyl, alkynyl, through substituted alkynyl, amidino groups, amino, through substituted-amino, aminoacyl, aminocarbonyl oxygen base, aminocarbonyl amino, amino thio-carbonyl-amino, aryl, through substituted aryl, aryloxy, through substituted aryloxy, cycloalkyloxy, through substituted cyclo alkoxy, heteroaryloxy, through substituted heteroaryloxy, heterocyclic oxy group, through substituted heterocyclyloxy, carboxyl, carboxyl ester class, cyanic acid, thiol, alkylthio, through substituted alkane sulphur base, arylthio, through replace arylthio, heteroarylthio, through replace heteroarylthio, cycloalkylthio, warp replacement cycloalkylthio, heterocycle sulfenyl, through substituted heterocycle sulfenyl, naphthenic base, through substituted cycloalkyl, guanidine radicals, halogen, nitro, heteroaryl, through substituted heteroaryl, heterocycle, through substituted heterocycle, oxygen base carbonylamino, oxygen base thio-carbonyl-amino ,-S (O) 2-alkyl ,-S (O) 2-through substituted alkyl ,-S (0) 2-naphthenic base ,-S (O) 2-through substituted cycloalkyl ,-S (O) 2-thiazolinyl ,-S (O) 2-through substituted alkenyl ,-S (O) 2-aryl ,-S (O) 2-through substituted aryl ,-S (O) 2-heteroaryl ,-S (O) 2-through substituted heteroaryl ,-S (O) 2-heterocycle ,-S (O) 2-through substituted heterocycle ,-OS (O) 2-alkyl ,-OS (O) 2-through substituted alkyl ,-OS (O) 2-aryl ,-OS (O) 2-through substituted aryl ,-OS (O) 2-heteroaryl ,-OS (O) 2-through substituted heteroaryl ,-OS (O) 2-heterocycle ,-OS (O) 2-through substituted heterocycle ,-OSO 2-NR 51R 51Each R wherein 51For hydrogen or alkyl ,-NR 51S (O) 2-alkyl ,-NR 51S (O) 2-through substituted alkyl ,-NR 51S (O) 2-aryl ,-NR 51S (O) 2-through substituted aryl ,-NR 51S (O) 2-heteroaryl ,-NR 51S (O) 2-through substituted heteroaryl ,-NR 51S (O) 2-heterocycle ,-NR 51S (O) 2-through substituted heterocycle ,-NR 51S (O) 2-NR 51-alkyl ,-NR 51S (O) 2-NR 51-through substituted alkyl ,-NR 51S (O) 2-NR 51-aryl ,-NR 51S (O) 2-NR 51-through substituted aryl ,-NR 51S (O) 2-NR 51-heteroaryl ,-NR 51S (O) 2-NR 51-through substituted heteroaryl ,-NR 51S (O) 2-NR 51-heterocycle and-NR 51S (O) 2-NR 51-through substituted heterocycle, each R wherein 51Be hydrogen or alkyl, wherein each term in this paper definition.
" aryloxy " refers to aryl-O-base, and the example comprises phenoxy, naphthyloxy and similar group thereof.
" through substituted aryloxy " refers to through substituted aryl-O-base." aryloxy aryl " refers to-aryl-O-aryl.
" through the substituted aryloxy aryl " refer to as above-mentioned for the definition through substituted aryl, by 1 to 3 substituting group at arbitrary or two nuclear substituted aryloxy aryl of fragrance.
" carboxyl " refers to-COOH or its salt.
" carboxyl ester class " refer to-C (O) O-alkyl ,-C (O) O-through substituted alkyl ,-C (O) O-aryl and-C (O) O-be through substituted aryl, wherein alkyl, through substituted alkyl, aryl and through substituted aryl in this paper definition.
" naphthenic base " refers to have the naphthenic base of 3 to 10 carbon atoms of single or polynary ring, and the example comprises adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, ring octyl group and similar group thereof.
" through substituted cycloalkyl " refers to have 1 to 5 substituent naphthenic base, and said substituting group is selected from by following each group of forming of base: ketone group (=0), thioketones base (=S), alkoxyl group, through substituted alkoxy, acyl group, amido, acyloxy, amino, through substituted-amino, aminoacyl, aryl, through substituted aryl, aryloxy, through substituted aryloxy, cyanic acid, halogen, hydroxyl, nitro, carboxyl, carboxyl ester class, naphthenic base, through substituted cycloalkyl, heteroaryl, through substituted heteroaryl, heterocycle with through substituted heterocycle.
" cycloalkyloxy " refers to-the O-naphthenic base.
" through substituted cyclo alkoxy " refer to-O-is through substituted cycloalkyl.
" halogen " or " halogen " refers to fluorine-based, chloro, bromo and iodo and is preferably fluorine-based or chloro.
" heteroaryl " refers to have 1 to 15 carbon atom, and preferable 1 to 10 carbon atom is selected from the heteroatomic aromatic base that oxygen, nitrogen and sulphur are formed group with interior 1 to 4 of ring.Said heteroaryl can have monocycle (for example pyridyl or furyl) or polynary fused rings (for example indolizine base or benzothienyl).Preferable heteroaryl comprises pyridyl, pyrryl, indyl, thienyl and furyl.
" through substituted heteroaryl " refers to by 1 to 3 substituted heteroaryl of substituting group, and said substituting group is selected from and the identical group of defined substituting group in substituted aryl.
" heteroaryloxy " refer to-and O-heteroaryl and " through substituted heteroaryloxy " refer to-and O-is through substituted heteroaryl.
" heterocycle " refers to have monocycle or polynary ring filling or the unsaturated group of condensing; It has 1 to 10 carbon atom and is selected from the heteroatoms that nitrogen, sulphur and oxygen are formed group with interior 1 to 4 of ring; Wherein in the condensed ring system; One or more ring can be aryl or heteroaryl, and restricted condition is that tie point is on heterocycle.
" through substituted heterocycle " refers to that by 1 to 3 substituted heterocycle of substituting group, said substituting group is identical with defined substituting group in substituted cycloalkyl.
The instance of heterocycle and heteroaryl includes, but is not limited to azetidine, pyrroles, imidazoles, pyrazoles, pyridine, pyrazine, pyrimidine, pyridazine, pyrrocoline, isoindole, indoles, indoline, indazole, purine, quinolizine, isoquinoline 99.9, quinoline, phthalazines, naphthyl pyridine (naphthylpyridine), quinoxaline, quinazoline, cinnolines, pteridine, carbazole, carboline, phenanthridines, acridine, phenanthroline, isothiazole, azophenlyene 、 isoxazole 、 phenoxazine, thiodiphenylamine, imidazolidine, tetrahydroglyoxaline, piperidines, piperazine, indoline, phthalic imidine, 1; 2; 3; 4-tetrahydrochysene-isoquinoline 99.9,4; 5; 6,7-tetrahydro benzo [b] thiophene, thiazole, thiazolidine, thiophene, benzo [b] thiophene, morpholinyl, thio-morpholinyl (thiomorpholinyl) (also being called as (thiamorpholinyl)), piperidyl, tetramethyleneimine, tetrahydrofuran base and similar group thereof.
" heterocyclic oxy group " refer to-and O-heterocycle and " through substituted heterocyclyloxy " refer to-and O-is through substituted heterocycle.
" thiol " or " sulfydryl " refers to-the SH base.
" alkylthio " refers to-the S-alkyl that wherein alkyl as above defines.
" through the substituted alkane sulphur base " refers to that as above defined-S-is through substituted alkyl.
" cycloalkylthio " refers to-the S-naphthenic base that wherein naphthenic base as above defines.
" through replacing cycloalkylthio " refer to-S-is through substituted cycloalkyl, and wherein as above defines through substituted cycloalkyl.
" arylthio " refer to-S-aryl and " through replacing arylthio " refer to-S-is through substituted aryl, aryl and as above define through substituted aryl wherein.
" heteroarylthio " refer to-S-heteroaryl and " through replacing heteroarylthio " refer to-S-is through substituted heteroaryl, heteroaryl and as above define through substituted heteroaryl wherein.
" heterocycle sulfenyl " refer to-S-heterocycle and " through the substituted heterocycle sulfenyl " refer to-S-is through substituted heterocycle, heterocycle and as above define through substituted heterocycle wherein.
Term " amino acid " refers to that (for example there is amino acid whose D-steric isomer in any amino acid and synthetic analogues that exists naturally naturally; D-Threonine for example) and its verivate; A-amino acid comprises a carbon atom, is connected with an amino, a carboxyl, a Wasserstoffatoms and a characteristic group that is called as " side chain " on it.Naturally exist amino acid whose side chain in this technology, to be known by us, for example hydrogen (for example in the glycocoll), alkyl (for example in L-Ala, Xie Ansuan, leucine, Isoleucine, the proline(Pro)), through substituted alkyl (for example in Threonine, Serine, methionine(Met), halfcystine, aspartic acid, l-asparagine, L-glutamic acid, Stimulina, l-arginine and the Methionin), arylalkyl (for example in phenylalanine(Phe) and the tryptophane), through substituted aryl alkyl (for example in the tyrosine) and heteroarylalkyl (for example in the Histidine).Non-natural amino acid is also known in this technology, for example Pei Geman publishing company (Pergamon Press) 1989 " synthesizing of optical activity alpha-amino acid " (the Synthesis of Optically Active.alpha.-Amino Acids) that edit by Williams that publish; People such as Evans, " american Journal of the Chemical Society " (J.Amer.Chem.Soc.), 112:4011-4030 (1990); People such as Pu, " american Journal of the Chemical Society ", 56:1280-1283 (1991); People such as Williams state in " american Journal of the Chemical Society ", 113:9276-9286 (1991); With all documents of wherein quoting.The present invention also comprises non-amino acid whose naturally side chain.
" pharmaceutically acceptable salt " refers to the pharmaceutically acceptable salt of compound; Said salt is to be derived to be the organic and inorganic counter ion that we knew in multiple this technology, and it comprises (only as an example) sodium, potassium, calcium, magnesium, ammonium, tetra-allkylammonium and similar group thereof; And when said molecule contained basic functionality, it was the salt of organic or inorganic acid, and for example hydrochloride, hydrobromate, tartrate, mesylate, acetate, PHENRAMINE MALEATE, oxalate and its type are saloid.
Term " prerequisite medicine " thus refer to the The compounds of this invention that comprises physiology and biocompatible removable group through modifying, said group removes so that active medicine, its pharmaceutically acceptable salt or its bioactive metabolites to be provided in vivo.Suitable removable group is known for us in this technology and preferable removable group comprises the ester of carboxylic moiety on the glycocoll substituting group.Said ester class is preferable to be comprised derived from the alkyl alcohols, through the ester of substituted alkyl alcohols, hydroxyl substituted aryl and heteroaryl etc.Another preferable removable group is the acid amides that is formed by the carboxylic moiety on the glycocoll substituting group.Suitable amide is derived from formula HNR 20R 21Amine, R wherein 20And R 21Independent be hydrogen, alkyl, through substituted alkyl, aryl, through substituted aryl and similar group thereof.
Should be appreciated that in all substituting groups of above definition; Through substituting group is defined as the polymkeric substance that has the substituting group that is same as self in addition and obtain (for example have one through substituted aryl as substituent through substituted aryl; Himself is replaced through substituted aryl by one, etc.) and be not included among this paper.Under said situation, said substituent maximum number is 3.That is to say that each above-mentioned definition is retrained by a restriction, for example through substituted aryl be limited to-through substituted aryl-(through substituted aryl)-through substituted aryl.
Should be appreciated that equally above-mentioned definition is not in order to comprise unallowed substitute mode (for example use 5 fluorine-based substituent methyls or with respect to ethene or the acetylene unsaturated link(age) hydroxyl as the α position).The substitute mode of said permission is known by the technician in said field.
Method of the present invention
The present invention provides the method for regulating HIF and/or EPO, thereby it stablizes HIF and the expression that activates the HIF regulatory gene through suppressing HIF α hydroxylation.Said method also can be applicable to prevention, treatment in advance or treatment HIF and/or EPO related conditions, comprises anaemia, local asphyxia and the anoxic patient's condition.
The treatment of HIF related conditions
Local asphyxia is two kinds of patient's condition relevant with HIF with anoxic and includes, but is not limited to myocardial infarction, liver local asphyxia, kidney local asphyxia and apoplexy; Surrounding blood vessel illness, ulcer, burn and chronic wounds; Pulmonary infarction; And ischemia reperfusion injury, comprise for example relevant ischemia reperfusion injury with operation and organ transplantation.In one embodiment, the present invention is provided at before local asphyxia or the anoxic, among or stablize the method for HIF α, particularly relevant local asphyxia or anoxic afterwards immediately with myocardial infarction, apoplexy or renal ischaemia-reperfusion injury.
One aspect of the present invention is provided for treating the method for the multiple local asphyxia and the anoxic patient's condition, particularly uses compound described herein.In one embodiment, when throwing was given after local asphyxia or anoxic, method of the present invention produced the treatment benefit.For example, after myocardial infarction, method of the present invention makes the reduction that M & M is surprising, and significantly improves cardiac structure and performance.On the other hand, when throwing was given after hepatogenotoxicity-ischemic injury, method of the present invention was improved liver function.Anoxic is an important component part of hepatic diseases, especially with the liver toxicity compound, for example in the relevant chronic hepatopathy of ethanol.In addition, knownly increased in alcoholic liver disease by the genetic expression of HIF α inductive, for example nitric oxide synthetase and glucose transporter-1.(see, people such as Areel for example, (1997) " hepatology " be 25:920-926 (Hepatology); Strubelt, (1984) " basis and applied toxicology " be 4:144-151 (Fundam.Appl.Toxicol.); Sato, (1983) " pharmacology, biological chemistry and behavior " (Pharmacol Biochem Behav) 18 (supplementary issue l): 443-447; People such as Nani, (1995) " American Journal of Pathology " be 146:329-334 (Am.J.Pathol.); With people such as Morio, (2001) " toxicology and drug application " be 172:44-51 (Toxicol.Appl.Pharmacol.)).
Therefore, the present invention provides the method for treatment local asphyxia or anoxic related conditions, and said method comprises gives the experimenter separately or with pharmaceutically acceptable excipient composition throwing with the compound of treatment significant quantity or its pharmaceutically acceptable salt.In one embodiment, said compound, for example myocardial infarction, pulmonary infarction, intestinal obstruction, ishemic stroke and renal ischaemia-reperfusion injury are given in throwing immediately after producing the ischemic patient's condition.In another embodiment; The patient who is diagnosed as the patient's condition relevant with chronic ischemic generation, for example cardiac cirrhosis, degeneration of macula, pulmonary infarction, acute respiratory failure, congenital alveolar dysplasia and congestive heart failure are given in said compound throwing.In another embodiment, said compound is given in throwing immediately after wound or damage.
Another aspect of the present invention provides the method for using compounds for treating described herein that the patient of generation local asphyxia or the danger of the anoxic patient's condition is arranged, the for example high-risk individuality of atherosclerosis.Atherosclerotic Hazard Factor comprise, for example hyperlipidaemia, smoking, hypertension, mellitus, hyperinsulinemia and abdominal obesity.Therefore, the present invention provides the method for prevention ischemic tissue injury, and said method comprises throws the patient who gives needs separately or with pharmaceutically acceptable excipient composition with the compound of treatment significant quantity or its pharmaceutically acceptable salt.In one embodiment, can give said compound, for example hypertension, mellitus, arteriosclerosis obliterans, chronic venous insufficiency, Raynaud disease, chronic skin ulcer, sclerosis, congestive heart failure and systemic sclerosis based on the throwing of procatarxis venereal disease condition.
In a particular embodiment, said method is used for increasing the vascularization and/or the granulation tissue formation of damaged tissue, wound and ulcer.For example, but compound of the present invention has been presented in the wound healing effective stimulus granulation tissue forms.Granulation tissue contains the seepage blood vessel and interim plasma proteins matrix of new formation, and for example Fibrinogen and PF are conjugated protein.Release from the growth factor of inflammatory cell, thrombocyte and activation endothelium stimulates inoblast and migration and the propagation of endotheliocyte in granulation tissue.If vascularization or nerve stimulation weaken, then ulcer can take place.Method of the present invention effectively promotes the formation of granulation tissue.Thereby, the present invention be provided for treating have since for example the tissue damage that causes of infraction, have by for example wound or damage inductive wound or have method owing to certain illness (for example mellitus) chronic wounds that produces or the patient of ulcer.Said method comprises throws the patient who gives needs separately or with pharmaceutically acceptable excipient composition with the compound of treatment significant quantity or its pharmaceutically acceptable salt.
Another aspect of the present invention provides and uses said compound to treat the method that the experimenter is taken place with minimizing or the prevention tissue damage relevant with local asphyxia or anoxic in advance.Before relating to the local asphyxia or the anoxybiotic patient's condition, throw immediately when giving, method of the present invention produces the treatment benefit.For example, before inducing myocardial infarction, use method of the present invention and show that cardiac structure and performance obtain the improvement of significance on statistics.On the other hand, when before the ischemia reperfusion injury and between throw immediately when giving, method of the present invention produces the treatment benefit, significantly reduces the Diagnostic parameters relevant with renal failure.
Therefore; The present invention provides and treats the method for experimenter with minimizing or the prevention tissue damage relevant with local asphyxia or anoxic in advance; Said method comprises gives the patient with ischemic conditions medical history separately or with pharmaceutically acceptable excipient composition throwing with the compound of treatment significant quantity or its pharmaceutically acceptable salt; Myocardial infarction for example, or have the patient of approaching ischemic conditions, for example stenocardia.In another embodiment, can possibly ischemic physical parameter throwing give said compound based on hint, for example for being under the general anesthesia or the individuality of temporary transient work under high height above sea level.In another embodiment, can said compound be used for organ transplantation, in order to treat organ donor in advance or before being implanted into acceptor, in order to keep the organ that removes from health.
Previous research shows that some compound that uses in the method for the invention is effective suppressor factor of procollagen prolyl 4-hydroxylase.Need reticular tissue in necrotic zone, to deposit although recognize the recovery of initial infraction or wound, the present invention's proof has no side effect for synulotic treatment.Thereby; Based on some compound of the present invention treatment and prevention oxygen-starved tissue damages and fibrosis on the benefit that provided; The present invention is contained a kind of treatment or is prevented to relate to " double treatment " method of the local asphyxia or the anoxic patient's condition; Comprise local asphyxia or the anoxic relevant, for example myocardial infarction and consequent congestive heart failure with the concurrent reaction fibrosis.Said method can be used a kind of compound, and it suppresses more than one and has phase homospecificity or not homospecific 2-oxoglutaric acid dioxygenase, for example HIF prolyl hydroxylase and procollagen prolyl 4-hydroxylase.Perhaps; Said method can be used combination of compounds; Wherein only a kind of 2-oxoglutaric acid dioxygenase of the special inhibition of each compound, for example a kind of compound special inhibition HIF prolyl hydroxylase and the second kind of special inhibition procollagen of compound prolyl 4-hydroxylase.
In one aspect, compound of the present invention suppresses one or more 2-oxoglutaric acid dioxygenases.In one embodiment, said compound inhibition has phase homospecificity or not homospecific 2-oxoglutaric acid dioxygenase family member, for example HIF prolyl hydroxylase and HIF l-asparagine-hydroxylase (FIH-1) at least two kinds.In another embodiment, said compound has specificity for a kind of 2-oxoglutaric acid dioxygenase, HIF prolyl hydroxylase for example, and demonstrate specificity seldom or do not show specificity for other family member.
Said compound can be thrown with multiple other treat-ment combination and give.In one embodiment, said compound and another kind of 2-oxoglutaric acid dioxygenase inhibitor are thrown together and are given, and wherein these two kinds of compounds have different specificitys for discrete 2-oxoglutaric acid dioxygenase family member.Said two kinds of compounds can be thrown with a ratio with respect to another simultaneously and give.Within the state of the art that is determined at said field for the ratio that is suitable for given therapeutic process or particular subject.Perhaps, said two kinds of compounds can be thrown continuously in the treatment time-histories and give, for example after myocardial infarction.In a particular embodiment, the activity of the special inhibition of a kind of compound HIF prolyl hydroxylase, and the activity of the second kind of special inhibition procollagen of compound prolyl 4-hydroxylase.In another specific embodiment, the activity of the special inhibition of a kind of compound HIF prolyl hydroxylase, and the activity of the second kind of special inhibition of compound HIF asparaginyl-hydroxylase.In another embodiment, said compound is thrown with another therapeutical agent with different effects pattern and is given, for example ACE inhibitor (ACEI), II Angiotensin II-II receptor blocking agent (ARB), statin, diuretic(s), digoxin, carnitine etc.
The treatment of EPO related conditions
The present invention provides the method that increases endogenous erythropoietin (EPO).These methods can be used in vivo, for example in the blood plasma, or in in-vitro application, for example in the cell culture medium of regulating.The present invention further provides the method that increases endogenous EPO content, in order to prevention, treatment in advance or treatment EPO related conditions, comprises for example relevant with anaemia and the neurological disorder patient's condition.The anaemia related conditions comprises the illness of for example acute or chronic renal disease, mellitus, cancer, ulcer, virus infection (for example HIV, bacterium or parasite), inflammation etc.The anaemia patient's condition can comprise further and the program or the relevant patient's condition of treatment that said program or treatment comprise for example radiotherapy, chemotherapy, dialysis and operation.The anaemia associated conditions comprises abnormal haemoglobin and/or red blood corpuscle in addition, for example is found in as in the illnesss such as microcytic anemia, hypochromic anemia, aplastic anemia.
The present invention can be used for preventative or increases the endogenous EPO among the experimenter who experiences particular treatment or program simultaneously, and the infected by HIV anaemia patient who is for example just treating with zidovudine or other RTI, acceptance contain the anaemia cancer patients of the cyclic chemical therapy of encircling Platinol (cisplatin) or not containing Platinol or anaemia or the non-anaemia patient that plan experience is performed the operation.The method of increase endogenous EPO also can be used for preventing, treats in advance or treatment and neural damage or the relevant EPO related conditions of nervous tissue degeneration, includes, but is not limited to apoplexy, wound, epilepsy, Spinal injury and neurodegenerative disorders.
In addition, said method can be used for the anaemia of increase plan experience operation or the endogenous EPO content among the non-anaemia patient, in order to reduce to the needs of external source blood transfusion or with so that the storage of the preceding blood of operation.The not stimulation of endogenous EPO or the compensatory erythropoietic increase of a small amount of minimizing of the blood hematocrit that before operation, after the body blood supply, takes place usually.Yet thorn is goaded effective increase red blood corpuscle quality into action and from body blood supply volume, is kept higher hematocrit levels simultaneously before the operation of endogenous EPO, and said method is specific is covered by among this paper.In some operation crowds, particularly operation is lost blood and is surpassed 2 liters individuality, can use method of the present invention and reduce allos blood and expose to the open air.Crosby (2002) " U.S.'s therapeutics journal (Amer.J.Therap.) 9:371-376.
Method of the present invention also can be used for strengthening exercise performance, improves exercising ability and promotion or strengthen aerobic and regulate.For example, the sportsmen can use said method can use said method to improve for example stamina and endurance to promote training and soldier.
Method of the present invention has shown in the substratum that can increase the external treatment culturing cell endogenous erythropoietin content in the animal plasma with interior therapeutic.Although kidney is the main source of erythropoietin in the body, once suitable stimulation, other organ comprises that brain, liver and marrow can and really can synthesize erythropoietin.Use method of the present invention can increase the expression of endogenous erythropoietin in a plurality of body members, comprise brain, kidney and liver.In fact, method of the present invention even be increased in the content of endogenous erythropoietin in the two animals of surveying nephrectomies of experience.
Even method proof of the present invention also can increase the content of erythropoietin when kidney function damage.Although the present invention limit by the mechanism that erythropoietin produces, visible erythropoietin excretory reduces the hyperoxia due to the increase that is attributable to flow in the nephridial tissue/pour in the renal failure process usually.People such as Priyadarshi, (2002) " international kidney journal (Kidney Int.) 61:542-546.
On the other hand, hematocrit and blood hemoglobin level in the animal of method increase interior therapeutic of the present invention.Along with compound uses and the increase of the blood plasma EPO, hematocrit and the blood oxyphorase that produce has dosage susceptibility in the method for the invention, yet can confirm that dosage is to produce the level of response of constant, controlled The compounds of this invention.On the other hand, use the treatment of The compounds of this invention can cure anaemia, for example by toxic chemical, chemotherapeutic Platinol inductive anaemia for example, or since the anaemia due to losing blood, for example wound, damage, parasite or operation.
In the animal with compounds for treating of the present invention, before hematocrit and the increase of blood oxyphorase, be the percentile increase of immature erythrocyte (reticulocyte) that circulates in the blood.Thereby, thereby the purposes in the method that the content of The compounds of this invention reticulocyte in increasing animal blood produces acellular reticulocyte lysate (like Pelham and Jackson at " european journal of biological chemistry " (Eur.J.Biochem.) described in the 67:247-256 (1976)) is contained in the present invention.Through with compound of the present invention separately treatment or with another kind of compound, combined therapy such as pyrodin for example, the content of circulation reticulocyte increases in the animal (for example rabbit etc.).Collect blood, and make the reticulocyte globulate and make cytolysis with zero(ppm) water through centrifugal.Extract can use the known proper method of any those skilled in the art to learn further processing, sees for example Jackson and Hunt, (1983) " method zymetology " (Methods Enzymol.) 96:50-74.
Method of the present invention can be used following general method and program, prepares from the starting substance that can obtain easily.Should be appreciated that when providing typical or preferable processing conditions (being temperature of reaction, time, reactant molar ratio, solvent pressure etc.), unless otherwise mentioned, also can use other processing conditions.The peak optimization reaction condition can change with employed specific reactants or solvent, but said condition can be measured through conventional optimum procedure by the those skilled in the art.
In addition, for it will be apparent to those skilled in the art that: it is essential that the GPF (General Protection False base experiences improper reaction for some functional group of prevention.Be used for the appropriate protection base of multiple functional group and be used to protect conditions suitable to be known by us in this technology with the deprotection particular functional group.For example; John Wei Li father and son publishing company (New York) in the 2nd edition that published in 1991 by " the protection base in the organic synthesis " (Protecting Groups in Organic Synthesis) that T.W.Greene and G.M.Wuts showed in and to have described numerous protections in the document quoted basic
In addition, compound of the present invention contains one or more chiral centre usually.Therefore, can or be separated into pure stereoisomers with said compound in case of necessity, promptly independent enantiomer or diastereomer, or be the steric isomer enriched mixture.All described steric isomers (and enriched mixture) are included in the category of the present invention, only if indication is arranged in addition.Pure stereoisomers (or enriched mixture) can use optical activity starting substance or the stereoselectivity reagent known in this technology for example to prepare.Perhaps, the racemic mixture of said compound can use that for example chiral column chromatography, chirality resolving agent and similar approach thereof are separated.
Compound of the present invention is preferable through the preparation of convergence synthetic schemes: as illustrated in the following scheme 1, under conventional coupling condition, make amino individuality and substituted isoquinoline acetogenin chemical combination.
R, R ', R ", R " ', R 1, R 2, R 3, R 4, R 5And R aSuch as among this paper definition.
Pg 1Refer to suitable protection base, for example tert-butyl ester class or ortho ester class.
Scheme 1
In particular, in scheme 1, suitable replaces amine or its N-alkyl derivative (compound 2) chemical combination through replacing 3-protection carboxyl isoquinoline (compound 1) with stoichiometric at least and preferable excessive warp.Said being reflected under the conventional coupling condition of knowing in this technology carried out.In one embodiment, reaction is in the presence of the methanol solution of sodium methylate, under high reaction temperature and preferablely under refluxing, carry out.Continue reaction and accomplish substantially until it, this needs about 1 to 48 hour usually.Reaction is in case accomplish, and can for example neutralize through routine techniques, extracts, deposition, chromatography, filtration and similar approach reclaim compound 3; Perhaps not purified and/or separate and be used for next step.
Perhaps, through replacing 3-protection carboxyl isoquinoline (compound 1) and can carrying out through the conventional peptide coupling program of knowing in this technology through the coupling that replaces amine or its N-alkyl derivative (compound 2).This coupled reaction uses the coupling reagent of knowing to carry out usually, for example carbodiimide class, bop reagent (phosphofluoric acid benzotriazole-1-base oxygen base-three (dimethylamino) Phosphonium) and similar reagents.The instance of suitable carbodiimide class comprises NSC 57182 (DCC), 1-(3-dimethylamino-propyl group)-3-ethyl carbodiimide (DECI) and similar reagents.In case of necessity, also can use the polymkeric substance of carbodiimide coupling reagent to carry form, for example comprise " tetrahedron communication " (Tetrahedron Letters), 34 (48), the reagent described in 7685 (1993).In addition, also can use the coupling promotor of knowing to promote coupled reaction, for example N-hydroxy-succinamide, I-hydroxybenzotriazole and similar reagents.
Usually through with compound 1 (being generally free acid) in about 1 to about 2 normal coupling reagent and at least 1 equivalent; Preferable about 1 to about 1.2 normal compound 2 contacts in a kind of inert diluent and carries out this coupled reaction; Said thinner for example is methylene dichloride, chloroform, acetonitrile, THF, N, dinethylformamide and similar reagents.This reaction was generally being carried out about 12 to about 24 hours under the temperature between about 0 ℃ to about 37 ℃.Reaction is in case completion is reclaimed compound 3 through ordinary method, and said ordinary method comprises neutralization, extraction, deposition, chromatography, filtration and similar approach.
Perhaps, can with through replacing 3-protection carboxyl isoquinoline (compound 1) thus be converted into acid halide and compound 3 be provided said acid halide and compound 2 couplings.The acid halide of compound 1 can prepare through compound 1 is contacted with mineral acid halogenide, for example contacts with THIONYL CHLORIDE 97, phosphorus trichloride, phosphorus tribromide or phosphorus pentachloride or preferablely contacts with oxalyl chloride.The general solvent-free or mineral acid halogenide in inert solvent (for example methylene dichloride or tetracol phenixin) of about 1 to 5 molar equivalent or the oxalyl chloride of using carries out this reaction, is reflected under the temperature between about 0 ℃ to about 80 ℃ and carries out about 1 to about 48 hours.Also can in this reaction, use catalyzer, for example DMF.
Then with acid halide (not shown) and at least 1 equivalent, preferable about 1.1 to about 1.5 normal compounds 2 are in a kind of inert diluent (for example methylene dichloride), contact under the temperature between about-70 ℃ to about 40 ℃ about 1 to about 24 hours.This reaction is preferablely carried out in the presence of appropriate base, is used for the acid that cleaning reaction produces.The instance of appropriate base comprises tertiary amines, for example triethylamine, diisopropylethylamine, N-methyl-morpholine etc.Perhaps, reaction can use alkaline solution (for example sodium hydroxide etc.) to carry out under Xiao Te-Bao Man (Schotten-Baumann) type condition.Reaction comprises neutralization, extraction, deposition, chromatography, filtration and similar approach in case completion is reclaimed compound 3 through ordinary method.
In one embodiment, the nitrogen-atoms of isoquinoline 99.9 loop systems can be used to provide corresponding N-oxide compound (compound 4 and 5) through the routine techniques oxidation.Oxidation can use conventional oxidant to carry out under normal condition, for example metachloroperbenzoic acid or hydrogen peroxide.Such as in the scheme 1 narration, the N-oxide compound forms and can take place through replacing on 3-protection carboxyl isoquinoline (compound 1) or the compound 3.
The starting substance that is used for scheme 1 reaction be commercially available maybe can be through the method preparation of knowing in this technology.For example glycocoll and N-alkyl glycocoll, like sarkosine, Ethylglycocoll etc. available from the Aldrich Chemical company (" Aldrich ") that is positioned at the Wisconsin, USA Milwaukee.
Synthesizing in this technology of substituted isoquinoline acetate also known, and is described in detail in people's such as Weidmann for example the USP the 6th, 093,730, and it is incorporated herein by reference in full.An ad hoc approach that is used for preparing said verivate is set forth in following scheme 2:
Figure BDA00001645958400511
Scheme 2
In particular, in scheme 2, commercially available 4-phenyl sulfenyl-phthalonitrile (compound 6) is hydrolyzed to corresponding diprotic acid (compound 7) under normal condition, for example handle with the 1:1 mixture of the 50%KOH aqueous solution/methyl alcohol.Continue reaction and accomplish substantially until it, this needs about 48 to 96 hours usually.Reaction is in case accomplish, the diprotic acid (compound 7) that can for example neutralize through routine techniques, extract, deposition, chromatography, filtration and similar approach reclaims gained; Perhaps not purified and/or separate and be used for next step.
Compound 7 cyclisation in the presence of the normal glycocoll of stoichiometric calculation.Be reflected in the solid phase and also then this mixture heating up to high temperature formation molten mass carried out through the uniform mixture that at first forms reagent.Reaction is preferable is heated to more than 200 ℃ and is more preferred from about 210 ℃ to about 220 ℃ for this.Continue reaction and accomplish substantially until it, this needs about 48 to 96 hours usually.Reaction is in case accomplish, the phthalic imidine (compound 8) that can for example neutralize through routine techniques, extract, deposition, chromatography, filtration and similar approach reclaims gained; Perhaps not purified and/or separate and be used for next step.
The conventional esterification of compound 8 produces compound 9, wherein R 8Be alkyl.This compound then stands circle amplification under alkaline condition.In particular, compound 9 is excessive with stoichiometry, and preferable 2 normal sodium alkoxides or alkanol potassium (for example sodium butylate) contacts and maintain about 70 ℃ extremely about 120 ℃ and be preferably about 95 ℃ extremely under about 100 ℃ high temperature in suitable solvent (for example propyl carbinol).Continue reaction and accomplish substantially until it, this needs about 0.5 to 6 hour usually.Reaction is in case accomplish, the isoquinoline 99.9 isomer (compound 9 and 10) that can for example neutralize through routine techniques, extract, deposition, chromatography, filtration and similar approach reclaims gained; Perhaps not purified and/or separate and be used for next step.
Above-mentioned reaction conditions can cause ester functional group's transesterification (if R 8Be not normal-butyl).Under any circumstance, the moieties of ester group is as the appropriate protection base of carboxyl-functional base on the compound 9 and in the compound 1 of scheme 1, be stated as Pg 1
The derivatives of being known in numerous these technology of hydroxyl-functional base experience on obvious 1.Suitable derive comprise form alkoxyl group, through substituted alkoxy, aryloxy, through substituted aryloxy, heteroaryloxy, through substituted heteroaryloxy, heterocyclic oxy group, through substituted heterocyclyloxy, halogenation, dehalogenation (on this position, hydrogen being provided), alkyl, through substituted alkyl, aryl, through substituted aryl, heteroaryl, through the substituted heteroaryl product.On the other hand, can use the program of approving in this technology to modify hydroxyl to provide-N (R 7) the R verivate, this can realize through halogen substituting group and suitable amine are reacted.Likewise; The sulfenyl verivate of sulfenyl and oxidation can prepare through ordinary method; For example, then make the sulfhedryl of gained and a kind of alkylating reagent (for example iodic ether and similar reagents thereof) reaction produce the alkylthio verivate according to circumstances with hydroxyl and thiophosphoric anhydride, lawesson reagent (Lawesson ' s reagent) or similar reagents reaction.The sulfenyl verivate can be further by standard peroxy acid reagent (for example-chlorine peroxybenzoic acid) oxidation.
On the other hand, the replacement on the isoquinoline compound phenyl ring is reached through suitable selection starting substance.Many in the said starting substance are commercially available, for example 4-phenoxy-phthalonitrile (Aldrich) etc.Perhaps, for example the compound of 4-(2, the 6-dimethyl phenoxy)-phthalonitrile can prepare through the technology of approving in this technology.
Perhaps, available commercially available through replacing the compound 7 in Tetra hydro Phthalic anhydride or the phthalic acid alternative scheme 1.Said acid anhydrides comprises, for example 3-difluorophthalic anhydride (Aldrich), 3-nitrophthalic acid acid anhydride (Aldrich), 3-chloro-phthalic anhydride (TCI America, Portland OR 97203 " TCI ") etc.Said acid comprises, for example 4-trifluoromethyl-phthalic acid (TCI) etc.
Test and the test of dispensing biology
The BA of The compounds of this invention can be estimated through the currently known methods that uses any routine.Suitable analytical procedure is known by us in this technology.Proposing following analysis only is not intended to limit as an example.Compound of the present invention is active in below at least a, analyzing.
HIF α stability analysis based on cell
The human cell who is derived from multiple tissue is inoculation and in 37 ℃, 20%O respectively in the culture dish of 35mm 2, 5%CO 2Under grow up in standard culture for example DMEM, 10%FBS.When cellular layer reaches when converging, with OPTI-MEM substratum (Invitrogen Life Technologies, Carlsbad CA) replace this substratum and with cellular layer in 20%O2,5%CO2, cultivating about 24 hours under 37 ℃.Then compound or 0.013%DMSO are added into existing substratum and continue cultivation whole night.
After the cultivation, with substratum remove, centrifugal and store to be used for analyzing (seeing following VEGF and EPO analysis).Cell is cleaned in cold phosphate buffered saline (PBS) (PBS) twice and then on ice in the middle cytolysis of the 10mM of 1ml Tutofusin tris (pH 7.4), 1mM EDTA, 150mM NaCl, 0.5%IGEPAL (Sigma-Aldrich, St.Louis MO) and protease inhibitor cocktail (Roche Molecular Biochemicals) 15 minutes.Cell lysates in 4 ℃ 3, under the 000xg centrifugal 5 minutes, and collecting cell solute segment (supernatant).Resuspending nucleus (coccoid) and cytolysis are in 20mM HEPES (pH 7.2), 400mM NaCl, 1mM EDTA, 1mM WR 34678 and the protease inhibitor cocktail (Roche Molecular Biochemicals) of 100 μ l; In 4 ℃ 13; Under the 000xg centrifugal 5 minutes, and collecting cell nucleoprotein segment (supernatant).
Use QUANTIKINE immunoassay (R&D Systems, Inc., Minneapolis MN) and come analysis of cells to examine pulsating HIF-1 α according to the indication of manufacturer.
Based on the VEGF of cell and the elisa assay of EPO
Use QUANTIKINE immunoassay (the R&D Systems that is fit to; Inc., Minneapolis MN) and according to the indication of manufacturer analyze collection from the vascular endothelial growth factor (VEGF) of the warp adjusting substratum of above-mentioned cell cultures and/or the expression of erythropoietin (EPO).
Oxygen consumption is analyzed
Oxygen sensor Tissue Culture Plate (BD Biosciences) contains and when anoxic, has more epipolic ruthenium complex.Therefore, when having the oxygen consumption cell in the plate, it changes into lower oxygen saturation and the fluorescence of Geng Gao with balance, reads thereby increase fluorescence.We estimate: the compound of stablizing HIF through the inhibition hydroxylation can reduce oxygen consumption to the consumption of oxygen and/or through cellular metabolism is changed the anaerobism production capacity by aerobic production capacity through reducing hydroxylation self.
At 37 ℃, 10%CO 2Make down and be derived from fetal kidney epithelium (293A) or uterine cervix epithelium gland cancer (HeLa) (the American Type Culture Collection that adenovirus transforms; Manassas VA) human cell is at substratum (high glucose DMEM (Mediatech; Inc., Herndon VA), 1% penicillium mould (penicillin)/Streptomycin sulphate (streptomycin) mixture (Mediatech), 1% fetal bovine serum) in grow to and converge.Collecting cell and in substratum with the density resuspending of 500,000 cells/ml.With cell suspending liquid with the 0.2ml/ pore distribution in each hole of oxygen biosensor 96 porocyte culture plates (BD Biosciences, Bedford MA).The following handled thing of 10 μ l volumes is added in three groups of holes: (1) 0.5%DMSO; (2) 200 μ M sodium lauryl sulphate; Or (3) 1,10 or 50 μ M compound.
In 37 ℃, 10%CO 2Under cultivate culture 72 hours and then in FL600 fluorometer (Biotek Instruments, Inc., Winooski VT), under the emission wavelength of the excitation wavelength of 485nm and 590nm, read culture plate.Control (O with the folding function that changes with respect to DMSO 2Consume) or the specific absorption under the 450nm wavelength (WST-1) is mapped data and use EXCEL software (Microsoft Corporation, Bellevue WA) to carry out the descriptive statistics analysis.
HIF-PH2 (PHD2) analyzes
Material
HIF-PH2 (EGLN1) is from the Hi5 cell expressing and through SP ion-exchange chromatography partial purification.Ketoisocaproic-[1-14C]-sodium salt derives from Perkin-Elmer.The alpha Ketoglutarate sodium salt is available from SIGMA.DLD 19 peptide (ethanoyl-DLDLEMLAPYIPMDDDFQL-CONH that the HPLC purifying is crossed 2) make by Synpep.
HIF-PH2 (EGLN2) is from insect Hi5 cell expressing and through SP ion-exchange chromatography partial purification.Catch through using the analysis of describing by Kivirikko and Myllyla (1982, " method zymetology " (Methods Enzymol) 82:245-304) 14CO 2Measure enzymic activity.Analytical reaction contain 50mM HEPES (pH 7.4), 100 μ M α-Tong Wuersuan sodium salts, 0.30 μ Ci/ml ketoisocaproic μ-[1- 14C]-sodium salt (Perkin Elmer, Wellesley MA), 40 μ M FeSO 4, 1mM ascorbate salt, 1541.8 units/ml katalase, have or do not have 50 μ M peptide matrix (ethanoyl DLDLEMLAPYIPMDDDFQL-CONH 2) and the compound of the present invention of different concns.Reaction begins through adding the HIF-PH2 enzyme.
Conversion percentage ratio when lacking peptide through deducting the conversion percentage ratio when having the matrix peptide calculates peptide dependency conversion percentage ratio.The peptide dependency conversion percentage ratio of use under given inhibitor concentration calculates and suppresses percentage ratio and IC 50Use GraFit software (Erithacus Software Ltd., Surrey UK) to calculate the IC of each suppressor factor 50Value.
Medicine prescription and dosing way
Compsn of the present invention can directly be carried or carry in medical composition together with suitable supporting agent or the vehicle known in this technology.Prior treatment method can comprise the experimenter that the The compounds of this invention of significant quantity is offerd medicine and dialysed or perform the operation and suffer from anaemia or anaemia danger is arranged to owing to for example chronic renal failure, mellitus, cancer, AIDS, radiotherapy, chemotherapy, kidney.In a preferred embodiment, the experimenter is a mammalian subject, and in an illustrated embodiments, the experimenter is the human experimenter.
The significant quantity of said medicament can be measured through normal experiment easily, equally the most effectively also can measure easily through normal experiment with the most convenient dosing way and the most suitable prescription.Multiple formulations capable of using and delivery system in this technology.See for example above-mentioned Gennaro, the nineteen ninety-five that A.R. edits publishes " the Lei Shi pharmacy is complete works of "
Suitable dosing way can comprise, for example oral, per rectum, in mucous membrane, nose or intestines dispensing and parenteral delivery, comprise in intramuscular, subcutaneous, intramedullary injection and intrathoracic, the direct ventricle, in the intravenously, intraperitoneal, nose or intraocular injection.Medicament or its compsn can be with the part but not the mode of whole body throw and give.For example, a kind of proper drug can or be carried in a kind of targeted drug delivery system via injection, and said targeted drug delivery system is for example long-acting or lasting release formulation.
Any method that medical composition of the present invention can be thus known in the technology is made, for example mixing, dissolving, granulation, dressing, pulverizing, emulsification, the inclosure capsule through routine, seal or freeze drying process.As stated, compsn of the present invention can comprise the acceptable supporting agent of one or more physiology, for example is convenient to bioactive molecule is machined to vehicle and auxiliary agent in the preparation of medicinal use.
Suitable prescription depends on selected dosing way.For example, can in the aqueous solution, allocate said compsn, preferablely in the physiology compatible buffers, allocate, for example hanks' solution (Hanks ' solution), ringer's solution (Ringer ' s solution) or normal saline buffer solution for injection.For offeing medicine through mucous membrane or nose, the permeate agent that will be suitable for permeability barrier is used for prescription.Said permeate agent is generally known in this technology.In a preferred embodiment of the present invention, compound of the present invention prepares in order to oral prescription.For oral, can allocate said compound easily through the pharmaceutically acceptable supporting agent of knowing in active compound and this technology is made up.Said supporting agent can be the tablet that is used for experimenter's orally ingestible, pill, drageeing, capsule, liquid, gel, syrup, ointment, suspension-s etc. with formulated of the present invention.Said compound is also adjustable to be rectal compositions, for example contains the suppository or the enema,retention of conventional suppository base (for example theobroma oil or other glyceride type).
As solid excipients, add where necessary after the suitable auxiliary agents, the mixture and the processing granular mixture that grind gained according to circumstances can obtain the pharmaceutical preparation that is used to orally use to obtain the core of tablet or drageeing.Suitable vehicle is in particular weighting agent, and for example sugar comprises lactose, sucrose, N.F,USP MANNITOL or Sorbitol Powder; Cellulose preparation, for example W-Gum, wheat starch, rice fecula, potato starch, gelatin, tragacanth gum, methylcellulose gum, Vltra tears, Xylo-Mucine and/or Vinylpyrrolidone polymer (PVP).Can add disintegrating agent in case of necessity, for example cross-linked polyvinylpyrrolidone, agar or alginic acid or its salt, for example sodium alginate.Also comprise wetting agent, for example sodium lauryl sulphate.
The drageeing core has suitable dressing.Can use spissated sugar soln, it contains Sudan Gum-arabic, talcum, Vinylpyrrolidone polymer, carbopol gel, polyoxyethylene glycol and/or titanium oxide, lacquer solution and appropriate organic solvent or solvent mixture according to circumstances for this reason.Dyestuff or pigment can be added into tablet or drageeing dressing, in order to the various combination of identification or characterization active compound doses.
Be used for oral pharmaceutical preparation and comprise the push style capsule that makes by gelatin, and the soft seal capsule that makes by gelatin and softening agent (for example glycerine or Sorbitol Powder).The push style capsule can contain and weighting agent (for example lactose), tackiness agent (for example starch) and/or lubricant (for example talcum or Magnesium Stearate) and the stablizer blended activeconstituents of adding according to circumstances.In soft capsule, active compound solubilized or be suspended in the suitable liquid, for example wax, whiteruss or liquid macrogol.In addition, can add stablizer.The dosage of all formula of oral should be suitable for said dispensing.
In one embodiment, but compound transdermal administration of the present invention (for example passing through patch) or topical administration.In one aspect, of the present inventionly can comprise one or more penetration enhancers or other effector in addition, comprise strengthening the medicament that institute's compound of carrying moves through skin or local prescription.For example under the situation of needs location conveying, preferably through skin or topical administration.
For inhalation dosing; Can use suitable propelling agent form with aerosol spray from pressurized package or atomizer to carry expediently according to compound used in the present invention, said propelling agent is dichloro two fluoro methane, trichlorofluoromethane, dichloro tetrafluoro ethane, carbonic acid gas or any other suitable gas for example.Under the situation of pressurised aerosol, the dose unit that is fit to can be confirmed with the amount of conveying and metering through a valve is provided.The capsule and the cartridge case of the adjustable for example gelatin that in sucker or insufflator, uses.These capsules and cartridge case contain the powdered mixture and the suitable powder matrix of compound, for example lactose or starch usually.
To be used for, for example come the compsn of parenteral admistration to exist by unit dosage form through allotment, for example be present in together in the ampoule or in multi-dose container with the sanitas that adds through bolus injection or lasting infusion through injection.Said compsn can be taked the form like the emulsion in suspension-s, solution or oil or the hydrophily agent, and can contain the for example blender of suspension agent, stablizer and/or dispersion agent.The prescription that is used for parenteral admistration comprises the compsn of the aqueous solution or other water-soluble form.
The suspension-s of active compound also can be prepared as suitable oily injection suspensions.Suitable lipophilic solvent or mediator comprise fatty oils, for example til and Acrawax class, for example OE or tri-glyceride or liposome class.Water injection suspension liquid can contain the material that increases suspension-s viscosity, for example Xylo-Mucine, Sorbitol Powder or Expex.Said suspension-s also can contain the reagent of suitable stabilizers or increase compound dissolution degree according to circumstances in order to the highly spissated solution of preparation.Perhaps, activeconstituents can be powder type, in order to before use with suitable mediator, for example sterile pyrogen-free water combination.
As stated, can be prolonged action preparation also with formulated of the present invention.The prescription of said long term can be thrown through implantation (for example subcutaneous or intramuscular) or through intramuscularly and give.Thereby compound for example of the present invention can be allocated with suitable polymerization or lyophobic dust (for example can accept to be emulsion form in the oil) or ion exchange resin, or is allocated as the slightly soluble verivate, for example slightly soluble salt.
The suitable supporting agent that is used for hydrophobic molecule of the present invention is known by us and is comprised the cosolvent system in this technology, and it comprises for example phenylcarbinol, a kind of non-polar surfactant, a kind of organic polymer and water that can be miscible with water.The cosolvent system can be VPD cosolvent system.VPD is the solution of 3%w/v phenylcarbinol, 8%w/v non-polar surfactant polysorbate 80 and 65%w/v Liquid Macrogol constant volume in absolute ethyl alcohol.VPD cosolvent system (VPD:5W) is made up of the VPD of 5% D/W 1:1 dilution.This cosolvent system is solubilizing hydrophobic property compound and when the whole body administration, produce hypotoxicity effectively.The ratio of cosolvent system can change greatly naturally and not destroy its solubleness and toxic characteristic.In addition, cosolvent component itself can change.For example, can use other hypotoxicity non-polar surfactant to replace polysorbate 80; The clip size of polyoxyethylene glycol can change; Other bioavailable polymer can replace polyoxyethylene glycol, for example Vinylpyrrolidone polymer; And other carbohydrate or polyose instead glucose.
Perhaps, can use other to be used for the delivery system of hydrophobic molecule.Liposome and emulsion be used for hydrophobic drug conveying mediator or supporting agent know instance.In above content, the liposome delivery system has been discussed about gene delivery system.Although the toxicity that Chang Yigeng is big is cost, also can use some organic solvent, for example methyl-sulphoxide.In addition, can use sustained release system to carry said compound, for example contain the semi-permeable matrix that significant quantity waits to throw the solid hydrophobic property polymkeric substance that gives compsn.Confirmed multiple sustained-release material and can be the those skilled in the art to utilize.Depend on its chemical property, lasting release capsule can discharge several Zhou Zhizhi of compound more than 100 days.The chemical property and the biological stability that depend on therapeutical agent can be used other strategy for protein stability.
For any compsn that is used for this treat-ment, can use the technology of knowing in multiple this technology to estimate the treatment effective dose at first.For example, in cell culture assays, can in animal model, design dosage reaching the circulation composition scope, the IC that it is included in the cell cultures to be measured 50The dosage range that is suitable for the human experimenter can for example use the data that from cell cultures and other zooscopy, obtain to confirm.
A kind of treatment effective dose of medicament instructs the pharmaceutical quantities that causes doing well,improving or experimenter's prolonged survival period.The toxicity of said molecule is renderd a service and can be measured through standard medicine program in cell cultures or in the laboratory animal with treatment, for example through measuring LD 50(overall 50% lethal dose) and ED 50(overall 50% treatment effective dose).Toxic effect is a therapeutic index to the dosage ratio of result of treatment, and it can be expressed as LD 50/ ED 50Ratio.Preferably show the reagent of high therapeutic index.
Preferable being in of dosage comprises ED 50And have seldom in toxicity or the avirulent circulation composition scope.Depend on employed dosage form and the dosing way that is utilized, dosage can change in this scope.Consider the details of experimenter's patient's condition, should select definite prescription, dosing way and dosage according to known method in this technology.
Can adjust dosage and interval individually in order to the plasma content that is enough to by the active part of required adjusting endogenous erythropoietin plasma content to be provided, i.e. MEC (MEC).For each compound, MEC can change but can estimate from for example vitro data.Reach the necessary dosage of MEC and depend on personal feature and dosing way.Medicament or its compsn should use can be kept the scheme of plasma content more than MEC and throw and give in the treatment time length of the treatment time length of about 10-90%, preferable about 30-90% and the treatment time length between the best 50-90%.Under the situation of topical administration or selectivity absorption, effective partial concn of medicine maybe be irrelevant with plasma concns.Perhaps; The stimulation of endogenous erythropoietin can reach through following steps: 1) throw and give loading dose; Then throw and give maintenance dose; 2) throw and to give inductive dose, throw then and give lower maintenance dose in required target zone, keeping hematocrit, or 3 in target zone, to reach erythropoietin content rapidly) repeat the discontinuity administration.
Undoubtedly, the medicament that gives thrown or the amount of compsn depend on multiple factor, comprise the experimenter's who is treating sex, age and body weight, painful seriousness, dosing mode and prescriber's judgement.
In case of necessity, compsn of the present invention can be present in the packing or dispenser device of the one or more unit dosage forms that contain activeconstituents.For example, said packing or equipment can comprise metal or plastic foil, for example Blister Package.Said packing or dispenser device can be with the dispensing indications.Also can prepare and comprise the compsn of allocating the The compounds of this invention in compatible medical carrier, be placed in the proper container also labelled in order to treat the indicated patient's condition.The indicated suitable patient's condition can comprise that anaemia is the patient's condition, illness or the treatment of diseases of main sign on the label.
In view of the disclosure of this paper, of the present invention these with other embodiment as far as the those skilled in the art with understanding easily and being special expection.
Instance
Through can further understanding the present invention with reference to following instance, said instance is purely in order to demonstration the present invention.The present invention is not restricted in the category of example embodiment, and it is only in order to the explanation of conduct to single aspect of the present invention.Any on the function equivalence method all in category of the present invention.Except modification described herein, will become obvious for the those skilled in the art through description and accompanying drawing multiple modification of the present invention before.In the said category that is modified in the accessory claim book.
Unless otherwise mentioned, otherwise all temperature be degree centigrade.And, have following implication in other local abbreviation that occurs of these instance neutralizations:
Figure BDA00001645958400581
Instance A-1
(S)-2-[(6-benzyloxy-1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid
A. (S)-2-[(6-benzyloxy-1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-methyl propionate
Under room temperature at 15ml CH 2Cl 2Benzyloxy-1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid (can be according to people's such as Weidmann USP 6 for middle stirring 0.33g 6-; 093; 730; 10/1998 acquisition), 0.5ml triethylamine, 0.38g HATU and the commercially available L-alanine methyl ester of 0.151g hydrochloride 18h; (elutriant=4:1 hexane-EtOAc) produces solid (S)-2-[(6-benzyloxy-1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-methyl propionate 0.220g that is white in color, MS-(+)-ion, M+1=415.8amu afterwards at silica gel chromatography.
B. (S)-2-[(6-benzyloxy-1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid
At room temperature stir 0.200g instance A-1a) described in (S) methyl esters and 15ml1.5M NaOH methanol solution 3h and concentrate.Resistates is dissolved in the water and extracts with EtOAc.With hydrochloric acid water layer is acidified to the pH value and is about 1 also through filtering the throw out of collecting gained; Water cleans; Dry 0.174g (S)-2-[(6-benzyloxy-1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid that is creamy white with generation in vacuum drying oven (70 ℃); MS-(+)-ion, M+1=401.0amu.
Instance A-2
(R)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-3-hydroxyl-propionic acid
A. (1,3-dioxy-1,3-dihydro-isoindole-2-yl)-butylacetate
The mixture of 160ml butanols, 20.0g (1,3-dioxy-1,3-dihydro-isoindole-2-yl)-acetate (94.6mmol) and the 2.0ml vitriol oil 24h that under agitation refluxes.Then by part adding a 5g sodium hydrogencarbonate, continue at room temperature to stir 5min and evaporating solvent in a vacuum.Resistates is divided in 100ml water and 100ml ETHYLE ACETATE to be dissolved.Clean organic phase with 100ml salt solution, also evaporate in a vacuum to produce little yellow oil with after coagulation via dried over sodium sulfate.Obtain the 24.02g title compound; MS-(+)-ion:
B.1,4-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester
Under agitation 4.41g sodium (190mmol) is dissolved in the 250ml propyl carbinol.After sodium dissolves fully, make solution be cooled to envrionment temperature and under agitation add 24.0g (91.9mmol) (1,3-dioxy-1,3-dihydro-isoindole-2-yl)-butylacetate and be dissolved in the solution of 150ml butanols.With this solution at 30min internal heating to 100 ℃ and under this temperature, stir 1h.Then make this mixture be cooled to envrionment temperature and also store 18h at ambient temperature.Then the pH value of mixture is adjusted into 2 to 3 through under agitation adding the 2N aqueous hydrochloric acid.Continue to stir 30min, suction filtration solid ingredient then.Water thoroughly clean filter cake and under vacuum in 50 ℃ of dryings to produce white solid.Obtain the 17.75g title compound; MS-(+)-ion:
C.1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Stir 17.3g (66.2mmol) 1 at ambient temperature, the mixture 1h of 4-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester and 100ml phosphorus oxychloride also then under agitation slowly is heated to reflux temperature in 2h.This mixture of gentle reflux 30min under agitation.After being cooled to room temperature, evaporating excessive phosphorus oxychloride in a vacuum and resistates is dissolved in the 100ml ETHYLE ACETATE.This solution is under agitation injected the 300ml saturated sodium bicarbonate aqueous solution.Formed throw out removes through vacuum filtration.Separate organic phase and with the ethyl acetate extraction water of 3 * 100ml.Merge water via dried over sodium sulfate, filter through silicagel pad and also evaporate in a vacuum to produce brown oil with after coagulation.Obtain the 11.37g title compound; 1H NMR (CDC1 3): δ=11.91 (s, 1H), 8.41 (m, 1H), 8.29 (m, 1H), 7.83 (m, 2H), 4.49 (t, 2H), 1.84 (m, 2H), 1.48 (m, 2H), 0.99 (t, 3H).
D.1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid
The mixture 2h of 9.23g 1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (33mmol), 90ml 2.5N aqueous sodium hydroxide solution, water (20ml) and the ethanol (110ml) of under agitation refluxing.Then the pH value of mixture is adjusted into 2 through adding concentrated hydrochloric acid aqueous solution.In the interpolation process, through making the temperature of mixture remain on 20 ℃ with the ice bath cooling.Then continue to stir 1h, then through the isolated by vacuum filtration solid ingredient.Water clean filter cake and under vacuum in 85 ℃ of dryings to produce white powder.Obtain the 6.64g title compound; MS-(+)-ion: M+1=224.1amu.
E. (R)-3-tert.-butoxy-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid tert-butyl ester
122.5 μ l (0.7mmol) ethyl-di-isopropyl-amine under agitation are added in the mixture of 45mg (0.2mmol) 1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid, 76mg (0.2mmol) phosphofluoric acid benzotriazole-1-base-(two-dimethylamino-methylene radical)-oxygen (HBTU), 50.8mg (R)-2-amino-3-tert.-butoxy-propionic acid tert-butyl ester hydrochloride (0.2mmol) and 1ml methylene dichloride.Continue to stir 40h at ambient temperature.Use hexane: ETHYLE ACETATE (9: 1) is as elutriant, through flash column chromatography on silica gel from reaction mixture separated product to produce water white oil.Obtain the 27mg title compound; MS-(+)-ion: M+1=422.8amu.
F. (R)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-3-hydroxyl-propionic acid
Stir at ambient temperature 27mg (0.06mmol) (R)-the mixture 2h of 3-tert.-butoxy-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid tert-butyl ester and 2ml trifluoroacetic acid.Then evaporate excessive trifluoroacetic acid in a vacuum, resistates is dissolved in also concentrates this solution in the 2ml absolute ethyl alcohol in a vacuum to produce pale brown look solid.Obtain the 27mg title compound; MS-(+)-ion: M+1=310.9amu.
Instance A-3
(S)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-3-hydroxyl-propionic acid
Be similar to instance A-2e) and f), by from instance A-2d) l-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid with (S)-2-amino-3-tert.-butoxy-propionic acid tert-butyl ester hydrochloride prepares; MS-(+)-ion: M+1=310.9amu.
Instance A-4
(R)-2-[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-3-hydroxyl-propionic acid
Be similar to instance A-2e) and f); (can be by l-chloro-4-hydroxyl-6-isopropoxy-isoquinoline-3-carboxylic acid according to people's such as Weidmann USP 6; 093,730,10/1998 obtains) and (R)-2-amino-3-tert.-butoxy-propionic acid tert-butyl ester hydrochloride prepares; MS-(+)-ion: M+1=369.0amu.
Instance A-5
(S)-2-[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-3-hydroxyl-propionic acid
Be similar to instance A-2e) and f); (can be by l-chloro-4-hydroxyl-6-isopropoxy-isoquinoline-3-carboxylic acid according to people's such as Weidmann USP 6; 093,730,10/1998 obtains) and (S)-2-amino-3-tert.-butoxy-propionic acid tert-butyl ester hydrochloride prepares; MS-(+)-ion: M+1=369.0amu.
Instance A-6
(R)-2-[(1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-3-hydroxyl-propionic acid
Be similar to instance A-2e) and f); (can be by l-chloro-4-hydroxyl-7-isopropoxy-isoquinoline-3-carboxylic acid according to people's such as Weidmann USP 6; 093,730,10/1998 obtains) and (R)-2-amino-3-tert.-butoxy-propionic acid tert-butyl ester hydrochloride prepares; MS-(+)-ion: M+1=369.0amu.
Instance A-7
(S)-2-[(1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-3-hydroxyl-propionic acid
Be similar to instance A-2e) and f); (can be by l-chloro-4-hydroxyl-7-isopropoxy-isoquinoline-3-carboxylic acid according to people's such as Weidmann USP 6; 093,730,10/1998 obtains) and (S)-2-amino-3-tert.-butoxy-propionic acid tert-butyl ester hydrochloride prepares; MS-(+)-ion: M+1=369.0amu.
Instance A-8
2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-2-methyl-propionic acid
Be similar to instance A-1a) and b), by from instance A-2d) l-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid and 2-amino-2-methyl-methyl propionate hydrochloride prepare; MS-(+)-ion: M+1=308.9amu.
Instance A-9
2-[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-2-methyl-propionic acid
Be similar to instance A-1a) and b), prepare by l-chloro-4-hydroxyl-6-isopropoxy-isoquinoline-3-carboxylic acid (can obtain according to people's such as Weidmann USP 6,093,730,10/1998) and 2-amino-2-methyl-methyl propionate hydrochloride; MS-(+)-ion: M+1=367.0amu.
Instance A-10
(R)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-3-(lH-imidazol-4 yl)-propionic acid; Three fluoro-acetates
Be similar to instance A-2e); By from instance A-2d) l-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid with (R)-2-amino-3-(1-trityl-lH-imidazol-4 yl)-methyl propionate hydrochloride begins, and is similar to instance A-1b then) deprotection and then be similar to 2f) prepare; MS-(+)-ion: M-1=359.1amu.
Instance A-11
(S)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-3-(lH-imidazol-4 yl)-propionic acid; Three fluoro-acetates
Be similar to instance A-2e); By from instance A-2d) l-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid with (S)-2-amino-3-(1-trityl-lH-imidazol-4 yl)-methyl propionate hydrochloride begins, and is similar to instance A-1b then) deprotection and then be similar to 2f) prepare; MS-(+)-ion: M-1=359.1amu.
Instance A-12
(R)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-3-methyl-butyric acid
Be similar to instance A-1a) and b) prepare; MS-(-)-ion: M-1=321.1amu.
Instance A-13
(S)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-3-methyl-butyric acid
Be similar to instance A-2e) and f) prepare; MS-(+)-ion: M+1=323.0amu.
Instance A-14
(R)-2-[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-3-methyl-butyric acid
Be similar to instance A-2e) and f) prepare; MS-(+)-ion: M+1=381.1amu.
Instance A-15
(S)-2-[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-3-methyl-butyric acid
Be similar to instance A-2e) and f) prepare; MS-(+)-ion: M+1=381.0amu.
Instance A-16
(R)-2-[(1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-3-methyl-butyric acid
Be similar to instance A-2e) and f) prepare; MS-(+)-ion: M+1=381.0amu.
Instance A-17
(S)-2-[(1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-3-methyl-butyric acid
Be similar to instance A-2e) and f) prepare; MS-(+)-ion: M+1=381.0amu.
Instance A-18
(S)-2-[(6-benzyloxy-1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-3-methyl-butyric acid
Be similar to instance A-1a) and b) prepare; MS-(-)-ion: M-1=429.0amu.
Instance A-19
(R)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-3-phenyl-propionic acid
Be similar to instance A-2e) and f) prepare; MS-(+)-ion: M+1=371.0amu.
Instance A-20
(S)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-3-phenyl-propionic acid
Being similar to instance A-2e} and f} prepares; MS-(+)-ion: M+1=371.0amu.
Instance A-21
(R)-2-[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-3-phenyl-propionic acid
Be similar to instance A-2e) and f) prepare; MS-(+)-ion: M+1=429.0amu.
Instance A-22
(S)-2-[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-3-phenyl-propionic acid
Be similar to instance A-2e) and f) prepare; MS-(+)-ion: M+1=429.0amu.
Instance A-23
(R)-2-[(1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-3-phenyl-propionic acid
Be similar to instance A-2e) and f) prepare; MS-(+)-ion: M+1=429.0amu.
Instance A-24
(S)-2-[(1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-3-phenyl-propionic acid
Be similar to instance A-2e) and f) prepare; MS-(+)-ion: M+1=429.0amu.
Instance A-25
(R)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-3-(4-hydroxyl-phenyl)-propionic acid
Be similar to instance A-2e) and f) prepare; MS-(+)-ion: M-1=385.0amu.
Instance A-26
(S)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-3-(4-hydroxyl-phenyl)-propionic acid
Be similar to instance A-2e) and f) prepare; MS-(+)-ion: M+1=387.1amu.
Instance A-27
(R)-2-[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-3-(4-hydroxyl-phenyl)-propionic acid
Being similar to instance A-2e} and f} prepares; MS-(-)-ion: M-1=443.0amu.
Instance A-28
(S)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-3-(4-hydroxyl-phenyl)-propionic acid
Being similar to instance A-2e} and f} prepares; MS-(-)-ion: M-1=443.0amu.
Instance A-29
(R)-2-[(1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-3-(4-hydroxyl-phenyl)-propionic acid
Be similar to instance A-2e) and f) prepare; MS-(+)-ion: M+1=445.1amu.
Instance A-30
(S)-2-[(1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-3-(4-hydroxyl-phenyl)-propionic acid
Be similar to instance A-2e) and f) prepare; MS-(+)-ion: M+1=445.1amu.
Instance A-31
(R)-2-[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-valeric acid
Be similar to instance A-1a) and b) prepare; MS-(+)-ion: M+1=381.0amu.
Instance A-32
(S)-2-[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-valeric acid
Be similar to instance A-1a) and b) prepare; MS-(-)-ion: M-1=379.0amu.
Instance A-33
(R)-1-(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-tetramethyleneimine-2-formic acid
Be similar to instance A-2e) and f) prepare; MS-(+)-ion: M+1=321.0amu.
Instance A-34
(S)-1-(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-tetramethyleneimine-2-formic acid
Be similar to instance A-2e) and f) prepare; MS-(+)-ion: M+1=321.0amu.
Instance A-35
(R)-1-(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-tetramethyleneimine-2-formic acid
Be similar to instance A-2e) and f) prepare; MS-(+)-ion: M+1=379.1amu.
Instance A-36
(S)-1-(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-tetramethyleneimine-2-formic acid
Be similar to instance A-2e) and f) prepare; MS-(+)-ion: M+1=379.1amu.
Instance A-37
(R)-6-amino-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-caproic acid; Trifluoroacetate
Be similar to instance A-2e) and f) prepare; MS-(+)-ion: M+1=352.2amu.
Instance A-38
(S)-6-amino-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-caproic acid; Trifluoroacetate
Be similar to instance A-2e) and f) prepare; MS-(+)-ion: M+1=352.1amu.
Instance A-39
(R)-6-amino-2-[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-caproic acid; Trifluoroacetate
Be similar to instance A-2e) and f) prepare; MS-(+)-ion: M+1=410.1amu.
Instance A-40
(S)-6-amino-2-[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-caproic acid; Trifluoroacetate
Be similar to instance A-2e) and f) prepare; MS-(+)-ion: M+1=410.1amu.
Instance A-41
(R)-6-amino-2-[(1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-caproic acid; Trifluoroacetate
Be similar to instance A-2e) and f) prepare; MS-(+)-ion: M+1=410.1amu.
Instance A-42
(S)-6-amino-2-[(1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-caproic acid; Trifluoroacetate
Be similar to instance A-2e) and f) prepare; MS-(+)-ion: M+1=410.1amu.
Instance A-43
(R)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-succsinic acid
Be similar to instance A-1a) and b) prepare; MS-(+)-ion: M+1=338.9amu.
Instance A-44
(S)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-succsinic acid
Be similar to instance A-2e) and f) prepare; MS-(-)-ion: M-1=337.0amu.
Instance A-45
(R)-2-[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-succsinic acid
Be similar to instance A-1a) and b) prepare; MS-(+)-ion: M+1=397.0amu.
Instance A-46
(S)-2-[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-succsinic acid
Be similar to instance A-2e) and f) prepare; MS-(+)-ion: M+1=397.1amu.
Instance A-47
(R)-2-[(1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-succsinic acid
Be similar to instance A-1a) and b) prepare; MS-(+)-ion: M+1=397.0amu.
Instance A-48
1-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-cyclopropane-carboxylic acid
Be similar to instance A-1a) and b) prepare; MS-(-)-ion: M-1=305.0amu.
Instance A-49
1-[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-cyclopropane-carboxylic acid
Be similar to instance A-1a) and b) prepare; MS-(+)-ion: M+1=365.0amu.
Instance A-50
Two deuteriums-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
Under agitation with 70mg (0.25mmol) from instance A-2c) 1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester, 193mg (2.5mmol) glycocoll-2,2-d 2Mixture backflow 15h with the methanol solution of sodium methylate of 5ml 0.5N.Then evaporating solvent in a vacuum is dissolved in the 8ml water and resistates with this solution of ETHYLE ACETATE cleaning of 2 * 20ml.Through adding the 1N aqueous hydrochloric acid pH value of this solution is adjusted into 3 also with this mixture of ethyl acetate extraction of 3 * 20ml.This merges extract and concentrates in a vacuum to produce white solid via dried over mgso.Obtain the 61mg title compound; MS-(-)-ion: M-1=280.9amu.
Instance A-51
(R)-2-[(6-benzyloxy-1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid
A. (R)-2-[(6-benzyloxy-1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-methyl propionate
Be similar to instance A-1a), make 0.33g 6-benzyloxy-1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid and the coupling of 0.150g D-alanine methyl ester hydrochloride.Obtain 0.205g creamy white solid product, MS-(+)-ion, M+1=415.0amu.
B. (R)-2-[(6-benzyloxy-1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid
Be similar to instance A-1b) prepare 0.164g white solid: MS-(=)-ion, M+1=401.1amu.
Instance A-52
(S)-2-[(7-benzyloxy-1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid
A. (S)-2-[(7-benzyloxy-1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-methyl propionate
Be similar to instance A-1a), make 0.33g 7-benzyloxy-1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid and the coupling of 0.150g L-alanine methyl ester hydrochloride.Obtain the 0.264g white solid: MS-(+)-ion, M+1=415.amu.
B. (S)-2-[(7-benzyloxy-1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid
Be similar to instance A-1b) prepare 0.216g white solid: MS-(+)-ion, M+1=401.9amu.
Instance A-53
(R)-2-[(7-benzyloxy-1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid
A. (R)-2-[(7-benzyloxy-1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-methyl propionate
Be similar to instance A-1a), make 0.33g 7-benzyloxy-1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid and the coupling of D-alanine methyl ester.Obtain 0.246g creamy white solid: MS-(+)-ion, M+1=415.0amu.
B. (R)-2-[(7-benzyloxy-1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid
Be similar to instance A-1b) prepare 0.211g creamy white solid: MS-(+)-ion, M+1=401.0amu.
Instance A-54
(S)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid
A) (S)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-methyl propionate
In in the 15ml methylene dichloride, stirring 0.55g1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid, 1.5ml triethylamine, 0.55g DECI and 0.56g (L)-alanine methyl ester hydrochloride 72h under the room temperature.Reaction mixture is divided between ETHYLE ACETATE and water dissolve, separate organic layer also successively with the 1M HCl aqueous solution, saturated NaHCO 3The aqueous solution and the saturated NaCl aqueous solution clean.With dried over sodium sulfate organic layer, filtration and concentrated so that 0.133g creamy white solid product to be provided under vacuum.MS-(+)-ion, M+1=308.9 dalton.
B) (S)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid
Be similar to instance A-1b), with instance A-54a) described in the saponification/acidifying of 0.116g (S) methyl esters, produce the 0.087g white solid product: MS-(+)-ion, M+1=294.9amu.
Instance A-55
(R)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid
A. (R)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-methyl propionate
Be similar to instance A-54a), make 0.55g 1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid and 0.40g D-alanine methyl ester coupling and obtain 0.200g creamy white solid product: MS-(+)-ion, M+1=308.8amu.
B. (R)-2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid
Be similar to instance A-1b) prepare 0.127g white solid: MS-(+)-ion, M+1=294.9amu.
Instance A-56
(S)-2-[(6-isopropoxy-1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid
Be similar to instance A-1a) condition under, make 0.030g 6-isopropoxy-1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid and 0.046g HATU and 0.017g L-alanine methyl ester the reaction.At room temperature use 0.014g NaOH in methanol-water to handle crude product 2 day at 1: 1, be about 2 with 1M hcl acidifying to pH value then at 0.1ml.Collect product through filtering, water cleans and is dry to produce 0.023g creamy white solid: MS-(-)-ion, M-1=353.0amu.
Instance A-57
(R)-2-[(6-isopropoxy-1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid
Be similar to instance A-56, make 0.030g 6-isopropoxy-1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid and the hydrochloride coupling of D-alanine methyl ester and this product of hydrolysis to produce 0.022g creamy white solid: MS-(-)-ion, M-1=353.0amu.
Instance A-58
(S)-2-[(7-isopropoxy-1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid
Be similar to instance A-56, make the reaction of 0.040g 7-isopropoxy-1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid and 0.020g L-alanine methyl ester hydrochloride, produce the 0.047g white solid after with middle ester hydrolysis: MS-(-)-ion, M-1=353.1amu.
Instance A-59
(R)-2-[(7-isopropoxy-1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid
Be similar to instance A-56, make the reaction of 0.040g 7-isopropoxy-1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid and D-alanine methyl ester hydrochloride.As among the instance A-56 with middle ester products hydrolysis to produce the 0.042g white solid: MS-(-)-ion, M-1=353.0amu.
Instance A-60
2-(S)-{ [7-(4-chloro-phenoxy)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-propionic acid
A) 4-(4-chloro-phenoxy)-phthalonitrile
Make mixture backflow 3h in acetone (87ml) of 4-nitrophthalonitrile (5.0g), 4-chlorophenol (3.13ml) and salt of wormwood (7.99g).After filtering and concentrating, resistates is dissolved in the ETHYLE ACETATE (100ml).Clean this solution with NaOH (1N, 50ml * 3) and salt solution.Dry organic layer, filtration, concentrate and dilute with methylene dichloride.Filter and flushing through silicagel pad, produce the 5.7g title compound. 1H?NMR(200MHz,DMSO)δ8.09(d,J=9Hz,1H),7.83(d,J=2.6,1H),7.53(d,J=8.6Hz,2H),7.42(dd,J=2.8,8.6Hz,1H),7.24(d,J=8.6,2H)。
B) 4-(4-chloro-phenoxy)-phthalic acid
Mixture backflow 18h with 1.31g 4-(4-chloro-phenoxy)-phthalonitrile, 45% Pottasium Hydroxide (3.5ml) and methyl alcohol (3.5ml).Add 6N HCl the pH value is adjusted to 4.Filtering precipitate, water clean and are dry to produce the 1.45g title compound.MS-(-)-ion: M-1=291.0amu.
C) [5-(4-chloro-phenoxy)-1,3-dioxy-1,3-dihydro-isoindole-2-yl]-butylacetate
The mixture of 500mg 4-(4-chloro-phenoxy)-phthalic acid and the positive butyl ester of glycocoll (286mg) is heated 5min down at 250 ℃.Through chromatography, with methylene dichloride as elutriant with the reaction mixture purifying to produce the title compound of 436mg. 1H?NMR(200MHz,DMSO)δ7.48(d,J=8.6Hz,1H),7.59(d,J=9.0Hz,2H),7.46(m,2H),7.29(d,J=9.0Hz,2H),4.46(s,2H),4.16(t,J=6.2Hz,2H),1.61(m,2H),1.38(m,2H),0.92(t,J=7.0Hz,3H)。
D) 6-and 7-(4-chloro-phenoxy)-1,4-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance A-2b) prepare.Two kinds of mixture of isomers.MS-(-)-ion: M-1=386.1.
E) 1-chloro-6-and 7-(4-chloro-phenoxy)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance A-2c) prepare.Two kinds of mixture of isomers.MS-(-)-ion: M-1=404.2.
F) 6-and 7-(4-chloro-phenoxy)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester:
Mixture backflow 25min with l-chloro-6-and 7-(4-chloro-phenoxy)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (280mg), 0.27ml 57 weight %HI, Glacial acetic acid min. 99.5 (3ml) and red phosphorus (43mg).Then this mixture of dilute with water is used solid NaHCO 3Alkalize to the pH value be 8, with ethyl acetate extraction (2 times).Clean ethyl acetate layer with sodium metabisulfite solution, saturated sodium bicarbonate, dry and concentrated.Use hexane/ethyl acetate; Through chromatography purification to produce 7-(4-chloro-phenoxy)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (103mg; The compound of instance A-60a): MS-(-)-ion: M-1=370.3 and 6-(4-chloro-phenoxy)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (71mg, the compound of instance 60b): MS-(-)-ion: M-1=370.3.
G) 2-(S)-{ [7-(4-chloro-phenoxy)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-propionic acid
Be similar to instance A-50, through 7-(4-chloro-phenoxy)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (compound of instance A-60a) and L-L-Ala are prepared in 130 ℃ of reaction 20min in microwave reactor.MS-(-)-ion: M-1=385.1.
Instance A-61
2-(S)-{ [6-(4-chloro-phenoxy)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-propionic acid
Be similar to instance A-50, through 6-(4-chloro-phenoxy)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (compound of instance A-60b) and L-L-Ala are prepared in 130 ℃ of reaction 25min in microwave reactor.MS-(-)-ion: M-1=385.1.
Instance A-62
2-{ [7-(3,4-two fluoro-phenoxys)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-propionic acid
A) 5-(3,4-two fluoro-phenoxys)-isoindole-1, the 3-diketone
With 3,4-difluorophenol (650mg) and benzene azeotropic and be dissolved in the methanol solution of sodium methylate (0.5M, 10ml).Then decompression removes methyl alcohol under nitrogen.Then dry DMF (10ml) solution with 4-nitro phthalic imidine (769mg) is added in the mixture before.The mixture of gained is at refluxed under nitrogen 23h.With reaction cooled and add 80ml water.Filter the throw out of gained, water cleans (4 times) and dry title compound with generation 685mg.MS-(-)-ion: M-1=274.3.
B) [5-(3,4-two fluoro-phenoxys)-1,3-dioxy-1,3-dihydro-isoindole-2-yl]-butylacetate
With 5-(3,4-two fluoro-phenoxys)-isoindole-1,3-diketone (680mg), salt of wormwood (1g), propione (20ml) and methyl bromoacetate (295 μ L) are added into pressure tube.With the mixture heating up to 105 of gained ℃, continue 17h.With 20ml water diluting reaction thing and with ethyl acetate extraction (2 times).Dry organic layer also concentrates.Through silica gel chromatography, use 4: 1 hexane/ethyl acetate and 3: 1 hexane/ethyl acetate purified mixture to produce the 657mg title compound. 1H?NMR(200MHz,DMSO)δ7.95(d,J=9.0Hz,1H),7.64-7.41(m,4H),7.15-7.08(m,1H),4.44(s,2H),3.70(s,3H)。
C) 6-and 7-(3,4-two fluoro-phenoxys)-1,4-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance A-2b) prepare.Two kinds of mixture of isomers.MS-(-)-ion: M-1=388.1.
D) 1-chloro-6-and 7-(3,4-two fluoro-phenoxys)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance A-2c) prepare.Two kinds of mixture of isomers directly continue on for next step.
E) 6-and 7-(3,4-two fluoro-phenoxys)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
(50% is wet, 88mg) is added in ETHYLE ACETATE (4ml) solution of l-chloro-6-and 7-(3,4-two fluoro-phenoxys)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (220mg) also then to add ammonium formiate (340mg) with 10%Pd/C.The mixture heating up of gained is extremely refluxed, continue 0.5h.After the cooling, filter with the ETHYLE ACETATE diluted reaction mixture and through Celite pad.Concentrating filtrate also passes through chromatography and separates to produce 131mg 7-(3; 4-two fluoro-phenoxys)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (compound of instance A-62a) and 55mg 6-(3,4-two fluoro-phenoxys)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (compound of instance A-62b).
F) 2-{ [7-(3,4-two fluoro-phenoxys)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-propionic acid
Be similar to instance A-50, through 7-(3,4-two fluoro-phenoxys)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (compound of instance A-62a) and L-L-Ala are prepared over 3 days in 85 ℃ of reactions in pressure tube.MS-(+)-ion: M-1=389.2.
Instance A-63
2-(S)-[(4-hydroxyl-7-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid
A) 4-phenyl sulfenyl-phthalic acid
5.06g 4-phenyl sulfenyl-phthalonitrile (21.4mmol), the 10ml 50%KOH aqueous solution and 10ml methyl alcohol 3.5 days under agitation reflux.Then also use the concentrated hydrochloric acid acidifying with this mixture of dilution of 100ml water.The suction filtration precipitated product, water thoroughly cleans also in a vacuum in 60 ℃ of dryings.Obtain the 5.75g title compound; MS-(-)-ion: M-1=273.0.
B) (1,3-dioxy-5-phenyl sulfenyl-1,3-dihydro-isoindole-2-yl)-acetate
In mortar, 5.62g 4-phenyl sulfenyl-phthalic acid (20.5mmol) and 1.55g glycocoll (20.5mmol) are thoroughly ground together.Then in oil bath with this mixture heating up to 210 ℃ to 220 ℃.Under this temperature, stir molten mass 15min, then it is cooled to envrionment temperature in a vacuum with scraper.Obtain the 6.30g title compound; MS-(-)-ion: M-1=311.8; 1H NMR (DMSO-d 6): δ=7.82 (d, 1H), 7.46-7.62 (m, 7H), 4.26 (s, 2H).
C) (1,3-dioxy-5-phenyl sulfenyl-1,3-dihydro-isoindole-2-yl)-methyl acetate
Under agitation with the mixture backflow 18h of 20ml methyl alcohol, 6.27g (1,3-dioxy-5-phenyl sulfenyl-1,3-dihydro-isoindole-2-yl)-acetate (20mmol) and the 0.3ml vitriol oil.Then add the dense sodium bicarbonate aqueous solution of 100ml also with this mixture of 100ml ethyl acetate extraction.Via MgSO 4Dry organic phase and evaporation in a vacuum.Obtain the 6.30g title compound; MS-(+)-ion: M+1=328.0; 1H NMR (CDC1 3): δ=7.69 (d, 1H), 7.41-7.55 (m, 7H), 4.40 (s, 2H), 3.75 (s, 3H).
D) 1,4-dihydroxyl-7-phenyl sulfenyl-isoquinoline-3-carboxylic acid butyl ester (A) and l, 4-dihydroxyl-6-phenyl sulfenyl-isoquinoline-3-carboxylic acid butyl ester (B)
Under agitation 0.92g sodium (40mmol) is dissolved in the 100ml propyl carbinol.Then temperature is increased to 95 ℃ to 100 ℃, adds 6.5g (1,3-dioxy-5-phenyl sulfenyl-1,3-dihydro-isoindole-2-yl)-methyl acetate (19.85mmol) and be dissolved in the hot soln in the 20ml propyl carbinol and under 95 ℃ to 100 ℃, continue to stir 1h.Evaporating solvent in a vacuum adds the 25ml 2N HCl aqueous solution and 100ml ETHYLE ACETATE and this mixture of vigorous stirring 1h, suction filtration then subsequently.Water thoroughly clean filter cake and under vacuum in 60 ℃ of dryings to produce the 4.43g yellow solid.On silica gel, use methylene dichloride through flash column chromatography: ETHYLE ACETATE (98:2) wash-out separates this A of 4.4g and the mixture of B.Evaporate first fraction and obtain 1.99gA; 1H NMR (CDC1 3): δ=10.48 (bs, 1H), 8.39 (bs, 1H), 8.24 (d, 1H), 8.01 (d, 1H), 7.35-7.55 (m, 6H), 4.39 (t, 2H), 1.77 (m, 2H), 1.46 (m, 2H), 0.99 (t, 3H).Evaporate second fraction and obtain 2.26g B; 1H NMR (CDC1 3): δ=10.38 (bs, 1H), 8.32 (bs, 1H), 8.24 (d, 1H), 7.86 (d, 1H), 7.37-7.56 (m, 6H), 4.39 (t, 2H), 1.77 (m, 2H), 1.46 (m, 2H), 0.99 (t, 3H).
E) 1-bromo-4-hydroxyl-7-phenyl sulfenyl-isoquinoline-3-carboxylic acid butyl ester
With 1.11g 1,4-dihydroxyl-7-phenyl sulfenyl-isoquinoline-3-carboxylic acid butyl ester (3mmol) is added in the solution that 4.59g bromine phosphorus oxide (16mmol) is dissolved in the 25ml anhydrous acetonitrile and with this mixture gentle reflux 1h under agitation.Then add 5.04g sodium hydrogencarbonate (60mmol), dropwise add 8ml water then.After stirring 90min at ambient temperature, mixture is concentrated into the about 1/3rd of its volume in a vacuum, adds 40ml water and with this mixture of 30ml ethyl acetate extraction.This mixture of suction filtration.Separate organic phase, via MgSO 4Dry also through the silicagel pad filtration.Evaporation in a vacuum produces the 0.885g title compound; 1H NMR (CDC1 3): δ=11.84 (s, 1H), 8.21 (d, 1H), 7.91 (d, 1H), 7.40-7.55 (m, 6H), 4.46 (t, 2H), 1.84 (m, 2H), 1.48 (m, 2H), 0.98 (t, 3H).
F) 4-hydroxyl-7-phenyl sulfenyl-isoquinoline-3-carboxylic acid butyl ester
Under agitation with the HI aqueous solution (3mmol) of 432mg 1-bromo-4-hydroxyl-7-phenyl sulfenyl-isoquinoline-3-carboxylic acid butyl ester (1mmol), 63mg red phosphorus (2mmol), 0.4ml 57 weight % and the mixture backflow 30min of 1ml Glacial acetic acid min. 99.5.Then,, use 0.2g NaHSO through the Celite pad suction filtration with 25ml ETHYLE ACETATE diluted reaction mixture 3The solution that is dissolved in 5ml water cleans and cleans twice with the dense sodium bicarbonate aqueous solution of 5ml.Via MgSO 4Dry organic phase and evaporation in a vacuum.Use hexane through flash column chromatography on the silica gel: ETHYLE ACETATE (85: 15) wash-out comes the purifying resistates.Obtain the 123mg title compound; 1H NMR (CDC1 3): δ=11.85 (s, 1H), 8.60 (s, 1H), 8.23 (d, 1H), 7.38-7.63 (m, 7H), 4.49 (t, 2H), 1.87 (m, 2H), 1.47 (m, 2H), 0.98 (t, 3H).
G) 2-(S)-[(4-hydroxyl-7-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid
4-hydroxyl-7-phenyl sulfenyl-isoquinoline-3-carboxylic acid butyl ester (0.20g) and the mixture heating up of L-L-Ala (0.75g) in 0.5M NaOMe/MeOH (11.3ml) are extremely refluxed, continue 36h.After the cooling, concentrated reaction mixture.Resistates is suspended in the water (50ml) and extracts with ETHYLE ACETATE (50ml), ethyl acetate layer is abandoned with 2N HCl acidified aqueous solution water layer.With ethyl acetate extraction (2 * 50ml).Merge organic layer, filtration and concentrated via dried over mgso to produce title compound (0.15g).MS-(-)-ion: M-1=367.1.
Instance A-64
2-(R)-[(4-hydroxyl-7-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid
Be similar to instance A-63g), through being reacted, 4-hydroxyl-7-phenyl sulfenyl-isoquinoline-3-carboxylic acid butyl ester and D-L-Ala prepare.MS-(-)-ion: M-1=367.1.
Instance A-65
2-(R)-[(4-hydroxyl-7-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid
A) 4-phenoxy-phthalic acid
Be similar to instance A-63a) synthetic by 4-phenoxy-phthalonitrile; MS-(-)-ion: M-1=256.9; 1H NMR (DMSO-d 6): δ=7.93 (d, 1H), 7.07-7.52 (m, 7H).
B) (1,3-dioxy-5-phenoxy-1,3-dihydro-isoindole-2-yl)-acetate
Be similar to instance A-63b) synthetic by 4-phenoxy-phthalic acid.MS-(+)-ion: M+1=297.9; 1HNMR (DMSO-d 6): δ=7.87 (d, 1H), 7.17-7.52 (m, 7H), 4.26 (s, 2H).
C) (1,3-dioxy-5-phenoxy-1,3-dihydro-isoindole-2-yl)-methyl acetate
Be similar to instance A-63c) synthetic by (1,3-dioxy-5-phenoxy-1,3-dihydro-isoindole-2-yl)-acetate; 1H NMR (CDC1 3): δ=7.83 (d, 1H), 7.05-7.46 (m, 7H), 4.41 (s, 2H), 3.76 (s, 3H).
D) 1,4-dihydroxyl-7-phenoxy-isoquinoline-3-carboxylic acid butyl ester (A) and l, 4-dihydroxyl-6-phenoxy-isoquinoline-3-carboxylic acid butyl ester (B)
Be similar to instance A-63d) synthetic by (1,3-dioxy-5-phenoxy-1,3-dihydro-isoindole-2-yl)-methyl acetate; Compd A: 1H NMR (CDCl 3): δ=10.58 (bs, 1H), 8.37 (bs, 1H), 8.14 (d, 1H), 7.87 (d, 1H), 7.05-7.49 (m, 6H), 4.39 (t, 2H), 1.77 (m, 2H), 1.46 (m, 2H), 0.99 (t, 3H); Compd B: 1H NMR (CDCl 3): δ=10.38 (bs, 1H), 8.38 (d, 1H), 8.28 (bs, 1H), 7.56 (d, 1H), 7.06-7.47 (m, 6H), 4.40 (t, 2H), 1.77 (m, 2H), 1.46 (m, 2H), 0.99 (t, 3H).
E) 1-bromo-4-hydroxyl-7-phenoxy-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance A-63e), by l, 4-dihydroxyl-7-phenoxy-isoquinoline-3-carboxylic acid butyl ester is synthetic; 1H NMR (CDCl 3): δ=11.89 (s, 1H), 8.35 (d, 1H), 7.63 (d, 1H), 7.08-7.52 (m, 6H), 4.47 (t, 2H), 1.84 (m, 2H), 1.48 (m, 2H), 0.99 (t, 3H).
F) 4-hydroxyl-7-phenoxy-isoquinoline-3-carboxylic acid butyl ester
Under hydrogen, stir the mixture 15h of 208mg 1-bromo-4-hydroxyl-7-phenoxy-isoquinoline-3-carboxylic acid butyl ester (0.5mmol), 49mg sodium acetate (0.6mmol), 50mg 10 weight % palladium charcoals, 10ml methyl alcohol and 5ml ETHYLE ACETATE in 1atm.Then through this mixture of Celite pad suction filtration and concentrated in a vacuum.Resistates is divided between 2ml half spissated bicarbonate aqueous solution and 8ml ETHYLE ACETATE to be dissolved.Via MgSO 4Dry organic phase.Evaporate in a vacuum and produce the 130mg title compound; 1H NMR (CDCl 3): δ=11.89 (bs, 1H), 8.61 (s, 1H), 8.36 (d, 1H), 7.10-7.53 (m, 7H), 4.49 (t, 2H), 1.87 (m, 2H), 1.47 (m, 2H), 0.98 (t, 3H).
G) 2-(R)-[(4-hydroxyl-7-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid
Be similar to instance A-63g), through under refluxad being reacted over 5 days, 4-hydroxyl-7-phenoxy-isoquinoline-3-carboxylic acid butyl ester and D-L-Ala prepare.MS-(-)-ion: M-1=351.1.
Instance A-66
2-(S)-{ [4-hydroxyl-7-(4-methoxyl group-phenoxy)-isoquinoline 99.9-3-carbonyl]-amino }-propionic acid
A) 4-(4-methoxyl group-phenoxy)-phthalonitrile
4-nitro-phthalonitrile (4.00g), 4-methoxyl group-phenol (3.46g) and the mixture heating up of salt of wormwood (6.39g) in acetone (64ml) to refluxing, are continued 2h.Reaction mixture is also filtered.Filtrate is concentrated and resistates is dissolved in the ETHYLE ACETATE (100ml).With NaOH (1N, 50ml), water and then clean this solution with salt solution.Merge organic layer, filtration and concentrated via dried over mgso to produce product (6.14g). 1H?NMR(200MHz,CDCl 3)δ6.70(d,J=7.8Hz,1H),7.21(m,2H),6.96(m,4H),3.84(s,3H)。
B) 4-(4-methoxyl group-phenoxy)-phthalic acid
Be similar to instance A-63a) prepare.MS-(-)-ion: M-1=286.9.
C) [5-(4-methoxyl group-phenoxy)-1,3-dioxy-1,3-dihydro-isoindole-2-yl]-methyl acetate
Be similar to instance A-63b) and c) prepare. 1H?NMR(200MHz,CDC1 3)δ7.74(d,J=8.6Hz,1H),7.25(m,2H),6.98(m,4H),4.40(s,2H),3.83(s,3H),3.75(s,3H)。
D) 6-and 7-(4-methoxyl group-phenoxy)-1,4-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance A-63d) prepare.MS-(+)-ion: M+1=384.10.
E) 6-and 7-(4-methoxyl group-phenoxy)-1-bromo-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance A-63e) prepare.MS-(+)-ion: M+1=448.05,446.05.
G) 7-(4-methoxyl group-phenoxy)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (A) and 6-(4-methoxyl group-phenoxy)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (B)
10 weight % palladium charcoals (wetting) (1.2g) are added in ETHYLE ACETATE (50ml) solution of above-claimed cpd (2.78g) and then add ammonium formiate (5.9g).The mixture 4h of backflow gained.After cooling, wash with its filtration and with ETHYLE ACETATE (100ml).With filtrate concentrate and through silica gel chromatography (33%-50% ETHYLE ACETATE in the hexane) purifying resistates to produce (0.74g) (MS-(+)-ion: M+1=368.16) and (1.11g) (MS-(+)-ion: M+1=368.17) of 6-(4-methoxyl group-phenoxy)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (B) of 7-(4-methoxyl group-phenoxy)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (A).
H) 2-(S)-{ [4-hydroxyl-7-(4-methoxyl group-phenoxy)-isoquinoline 99.9-3-carbonyl]-amino }-propionic acid
Be similar to instance A-63g), prepare by (instance A-66a's) 7-(4-methoxyl group-phenoxy)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester and L-L-Ala.MS-(-)-ion: M-1=381.13.
Instance A-67
2-(S)-[(7-benzenesulfonyl-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid
A) 7-benzenesulfonyl-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
With 7-phenyl sulfenyl-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (compound 363f) (165mg) and-(377mg) stirred overnight at room temperature of the mixture in methylene dichloride (5ml) of chlorine peroxybenzoic acid (77%).Filter reaction mixture.With methylene dichloride (20ml) dilution filtrate and continue with saturated sodium bicarbonate aqueous solution (2 * 20ml), water and salt solution cleaning.Via dried over mgso organic layer, filtration and concentrated.Through silica gel chromatography (with the 0%-20% eluent ethyl acetate in the methylene dichloride) purifying crude product to produce title compound 120mg.MS-(+)-ion: M+1=386.11.
B) 2-(S)-[(7-benzenesulfonyl-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid
Be similar to instance A-63g), prepare by 7-benzenesulfonyl-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester and L-L-Ala.MS-(-)-ion: M-1=399.1.
Instance A-68
(R)-2-[(4-hydroxyl-1-methoxymethyl-7-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid
A) 1-bromo-4-hydroxyl-7-phenoxy-isoquinoline-3-carboxylic acid
Under agitation with 1-bromo-4-hydroxyl-7-phenoxy-isoquinoline-3-carboxylic acid butyl ester (3.52g, 8.45mmol; Instance A-65e), the 2N NaOH aqueous solution (50ml, 100mmol) and the mixture backflow 2h of EtOH (50ml).Then concentrate the l/2 of this solution to its volume in a vacuum, water (180ml) dilution also passes through to add the 6N HCl aqueous solution (20ml) acidifying.Make the vacuum filtration of gained suspension-s after stirring 30min at ambient temperature.Water thoroughly clean filter cake in a vacuum in 70 ℃ of dryings with the generation solid title compound (3.05g) that is white in color; 1HNMR (DMSO-d 6): δ=8.33 (d, 1H), 7.20-7.61 (m, 7H).
B) 4-benzyloxy-1-methoxymethyl-7-phenoxy-isoquinoline-3-carboxylic acid benzyl ester
Under agitation (3.2ml, 8mmol) solution slowly is added into l-bromo-4-hydroxyl-7-phenoxy-isoquinoline-3-carboxylic acid (721mg is in anhydrous THF (100ml) solution 2mmol) in-78 ℃ of hexanes with the 2.5M n-Butyl Lithium.After stirring 5min again, add MeOCH 2I (357 μ l, 4mmol).15min is stirred in continuation again under-78 ℃, add the water (50ml) and the 6N HCl aqueous solution (1.5ml) then.Under agitation make this mixture temperature to envrionment temperature and then be concentrated into about 1/3 of its volume in a vacuum.Through adding the iodine that Sodium Pyrosulfite removes trace, use EtOAc (100ml) to extract this mixture then.Via MgSO 4Dry organic phase also concentrates to produce pale brown look solid (576mg) in a vacuum.The above-mentioned little yellow solid of the 570mg that under agitation refluxes, bromotoluene (0.97ml, 8mmol), K 2CO 3(2.76g, 20mmol) and the mixture of acetone (40ml) 3.5 days.Then concentrate in a vacuum.Water (15ml) is added in the resistates and extracts this mixture with EtOAc (60ml).Via MgSO 4Dry organic phase also concentrates to produce little yellow oil in a vacuum.On silica gel, use hexane: EtOAc=75 through flash column chromatography: 25 come purifying as elutriant, produce the title compound (490mg) that is yellow oil; MS-(+)-ion: M+1=506.2.
C) 4-benzyloxy-1-methoxymethyl-7-phenoxy-isoquinoline-3-carboxylic acid
Stir at ambient temperature 4-phenoxy-1-methoxymethyl-7-phenoxy-isoquinoline-3-carboxylic acid benzyl ester (480mg, 0.95mmol), KOH (325mg, 5mmol) and the mixture 48h of EtOH (10ml), evaporating solvent in a vacuum then.(10ml) is added in the resistates with water, and the 6N HCl aqueous solution comes this mixture of acidifying and (2 * 25ml) extract with EtOAc through adding.Via MgSO 4Dry merging organic phase also concentrates in a vacuum and is pale brown look solid title compound (355mg) with generation; MS-(-)-ion: M-1=414.1.
D) (R)-2-[(4-benzyloxy-1-methoxymethyl-7-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid tert-butyl ester
Under agitation with ClCO 2IBu (26.5 μ l, 0.2mmol) be added into ice bath refrigerative 4-benzyloxy-1-methoxymethyl-7-phenoxy-isoquinoline-3-carboxylic acid (79mg, 0.19mmol), NEt 3(56 μ l, 0.4mmol) and CH 2Cl 2In the mixture (5ml).After stirring 15min, and interpolation (R)-L-Ala tert-butyl ester hydrochloride (36mg, 0.2mmol) also under agitation whole night with this mixture temperature to envrionment temperature.Concentrate this mixture subsequently in a vacuum.Water (10ml) and several 6N HCl aqueous solution are added in the resistates.(2 * 15ml) extract this mixture with EtOAc.Via MgSO 4Dry organic phase also concentrates in a vacuum.On silica gel, use EtOAc to come purifying through flash column chromatography, produce the title compound (88mg) that is brown yellow oil as elutriant; MS-(+)-ion: M+23=565.2.
E) (R)-[(4-hydroxyl-1-methoxymethyl-7-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-tert.-butyl acetate
At H 2Under environmental stress and temperature, stir (R)-2-[(4-benzyloxy-1-methoxymethyl-7-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid tert-butyl ester (81mg under-the atmosphere; 0.15mmol), the mixture 18h of Pd/C (50mg, 10 weight %Pd), EtOAc (15ml).Then filter this mixture through Celite pad.Thoroughly clean zeyssatite and filter cake and concentrate the merging organic phase is brown yellow oil with generation title compound (63mg) in a vacuum with EtOAc; MS-(-)-ion: M-1=451.2.
F) (R)-2-[(4-hydroxyl-1-methoxymethyl-7-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid
Stir at ambient temperature (R)-[(4-hydroxyl-1-methoxymethyl-7-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-tert.-butyl acetate (59mg, 0.13mmol) and the mixture 4h of trifluoroacetic acid (4ml).Then concentrate this mixture in a vacuum and resistates is dissolved among the EtOH.Evaporating solvent is pale brown look solid title compound (52mg) with generation in a vacuum; MS-(+)-ion: M+1=397.1.
Instance A-69
(S)-2-[(4-hydroxyl-1-methoxymethyl-7-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid
A) (S)-2-[(4-benzyloxy-1-methoxymethyl-7-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid tert-butyl ester
Be similar to instance A-68d), synthetic by (S)-L-Ala tert-butyl ester and 4-benzyloxy-1-methoxymethyl-7-phenoxy-isoquinoline-3-carboxylic acid (instance A-68c); MS-(+)-ion: M+23=565.2.
B) (S)-2-[(4-hydroxyl-1-methoxymethyl-7-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid tert-butyl ester
Be similar to instance A-68e), synthetic by (S)-2-[(4-benzyloxy-1-methoxymethyl-7-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid tert-butyl ester; MS-(-)-ion: M-1=451.2.
C) (S)-2-[(4-hydroxyl-1-methoxymethyl-7-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid
Be similar to instance A-68f), synthetic by (S)-2-[(4-hydroxyl-1-methoxymethyl-7-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid tert-butyl ester; MS-(+)-ion: M+1=397.1.
Instance A-70
(S)-2-[(4-sulfydryl-7-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid
A) 4-dimethyl-thiocarbamyl oxygen base-7-phenoxy-isoquinoline-3-carboxylic acid butyl ester
For chloroformamide and 1.5g 1,4-diazabicyclo [2.2.2] octane is added into 1.5g 4-hydroxyl-7-phenoxy-isoquinoline-3-carboxylic acid butyl ester (instance A-65f) and is dissolved in the solution of 6.3ml dry DMF with the 578mg dimethyl sulphide.At room temperature stir this mixture whole night.Mixture is injected 30ml 1N HCl and divides 3 extractions with 30ml ETHYLE ACETATE.Water and salt solution clean organic part, via anhydrous sodium sulfate drying and concentrated to produce the 1.9g product; MS (+) m/z425.27 (M+1).
B) 4-dimethylamino formyl radical sulfenyl-7-phenoxy-isoquinoline-3-carboxylic acid butyl ester
The solution that 1.9g 4-dimethyl-thiocarbamyl oxygen base-7-phenoxy-isoquinoline-3-carboxylic acid butyl ester is dissolved in the 22ml phenyl ether is heated to 190 ℃, continues 2 hours.Under vacuum, concentrate this solution to produce thick resistates, it comes purifying with this product of 30-80% ETHYLE ACETATE gradient elution in the hexane through column chromatography on silica gel, produce 1.73g; MS (+) m/z 425.07 (M+1).
C) 4-sulfydryl-7-phenoxy-isoquinoline-3-carboxylic acid methyl esters
460mg 4-dimethylamino formyl radical sulfenyl-7-phenoxy-isoquinoline-3-carboxylic acid butyl ester is added in the methanol solution of 6.5ml 0.5N sodium methylate.Gained solution is heated to 50-60 ℃, continues 8 hours, be cooled to room temperature also with 10ml water and 7.0ml1N HCl dilution.Filter the yellow mercury oxide that this solution is collected gained through (medium) porous Bu Shi filter funnel, produce the 307mg product; MS (+) m/z 312.08 (M+1).
D) (S)-2-[(4-sulfydryl-7-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid
100mg 4-sulfydryl-7-phenoxy-isoquinoline-3-carboxylic acid methyl esters and 286mg L-L-Ala are added in the methanol solution of 6.0ml 0.5M sodium methylate.Use CEM Discover microwave reactor with this mixture heating up to 150 ℃, continue 15min.With 1N HCl gained solution is acidified to pH 3, with 10ml water dilution and use the 20ml ethyl acetate extraction.Clean organic part with salt solution, via anhydrous sodium sulfate drying and concentrated to produce the 114mg product; MS (-): m/z369.07 (M-1).
Instance A-71
(S)-2-{ [1-(4-chloro-phenyl sulfenyl)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-propionic acid
A) 1-bromo-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance A-65c)-e), prepare title compound by (1,3-dioxy-1,3-dihydro-isoindole-2-yl)-methyl acetate; 1H NMR (200MHz, CD 3OD) δ 11.89 (s, lH), 8.41 (m, 1H), 8.25 (m, 1H), 7.84 (m, 2H), 4.49 (t, J=7.0Hz, 2H), 1.87 (m, 2H), 1.47 (m, 2H), 1.00 (t, J=7.2Hz, 3H).
B) (S)-2-{ [1-bromo-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-propionic acid
400mg 1-bromo-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester and 890mg (L)-L-Ala are suspended in the methanol solution of 20ml 0.5M sodium methylate.Use CEM Discover microwave reactor with this mixture heating up to 160 ℃, continue 12min.With the extremely about 10ml of gained solution concentration, and add 0.5N HCl until reaching pH 3.With this solution of ethyl acetate extraction 3 times, and via organic part of dried over sodium sulfate and be concentrated into pale brown look solid; MS (-): m/z 337.14 (M-1).
C) (S)-2-{ [1-(4-chloro-phenyl sulfenyl)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-propionic acid
433mg 4-chloro-benzenethiol is added into 250mg (S)-2-{ [1-bromo-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-propionic acid is dissolved in the solution of 0.7ml1-N-methyl-2-2-pyrrolidone N-.Use CEM Discover microwave reactor that this solution is heated 30min down at 210 ℃.Under vacuum, concentrate this solution.Crystallization gained resistates is to obtain the pale brown look solid of 18mg from methyl alcohol; MS (-): m/z 401.10 (M-1).
Instance A-72
(R)-2-{ [1-(4-chloro-phenyl sulfenyl)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-propionic acid
Under the condition that is similar to instance A-71.b-c by l-bromo-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (instance A-71a) and (D)-L-Ala prepares title compound; MS (-): m/z 401.08 (M-1).
Instance A-73
(S)-2-{ [7-(3-fluoro-5-methoxyl group-phenoxy)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-propionic acid
A) 4-(3,4-two fluoro-phenoxys)-phthalonitrile
Be similar to instance A-60a) prepare. 1H?NMR(200MHz,DMSO)δ8.14(d,J=9Hz,1H),7.95(d,J=2.6,1H),7.56(dd,J=2.6,8.6Hz,1H),7.19(dt,J=2.4,9.2Hz,1H),7.04(m,2H)。
B) 4-(3-fluoro-5-methoxyl group-phenoxy)-phthalic acid
Be similar to instance A-60b) prepare.In hydrolysis, one fluorine-based is replaced by methoxyl group.MS-(-)-ion, M-1=305.0.
C) [5-(3-fluoro-5-methoxyl group-phenoxy)-1,3-dioxy-1,3-dihydro-isoindole-2-yl]-butylacetate
Be similar to instance A-60c) prepare. 1H?NMR(200MHz,DMSO)δ7.93(d,J=8.6Hz,1H),7.43(m,2H),6.79-6.63(m,3H),4.41(s,2H),4.10(t,J=6.2,2H),1.54(m,2H),1.30(m,2H),0.86(t,J=7.0,3H)。
D) 6-and 7-(3-fluoro-5-methoxyl group-phenoxy)-1,4-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance A-2b) prepare.Two kinds of mixture of isomers.MS-(-)-ion, M-1=400.1.
E) 1-chloro-6-and 7-(3-fluoro-5-methoxyl group-phenoxy)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance A-2c) prepare.Two kinds of mixture of isomers.MS-(-)-ion, M-1=418.3.
F) 6-and 7-(3-fluoro-5-methoxyl group-phenoxy)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance A-62e) prepare.The mixture of separating isomerism body is to produce 7-(3-fluoro-5-methoxyl group-phenoxy)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (compound of instance A-73a) and 6-(3-fluoro-5-methoxyl group-phenoxy)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (compound of instance A-73b). 1H?NMR(200MHz,CD 3OD)δ8.73(s,1H),8.15(d,J=9.0Hz,1H),7.71(s,1H),7.59(m,1H),6.65-6.47(m,3H),4.49(t,J=6.6Hz,2H),3.81(s,3H),1.87(m,2H),1.56(m,2H),1.03(t,J=7.4,3H)。
G) (S)-2-{ [7-(3-fluoro-5-methoxyl group-phenoxy)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-propionic acid
Be similar to instance A-50, through 7-(3-fluoro-5-methoxyl group-phenoxy)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (compound of instance A-73a) and L-L-Ala are prepared over 3 days in 90 ℃ of reactions in pressure tube.MS-(-)-ion: M-1=399.1.
Instance A-74
2-(S)-[(7-cyclohexyloxy-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid
A. (5-hydroxyl-1,3-dioxy-1,3-dihydro-isoindole-2-yl)-ETHYLE ACETATE
Be similar to instance D-100c), by 4-hydroxyl-phthalic acid and the preparation of glycine ethyl ester acetate. 1H?NMR?(200MHz,DMSO-d 6)δ11.0(br?s,1H),7.74(d,J=7.8Hz,1H),7.17(m,2H),4.35(s,2H),4,13(q,J=7.0Hz,2H),1.20(t,J=7.0Hz,3H)。
B. (5-cyclohexyloxy-1,3-dioxy-1,3-dihydro-isoindole-2-yl)-ETHYLE ACETATE
Hexalin (3.2g), diethyl azodiformate (6.9g) are added into (5-hydroxyl-1; 3-dioxy-1,3-dihydro-isoindole-2-yl)-mixture of ETHYLE ACETATE (8.0g) in anhydrous tetrahydro furan (160ml) in and then add triphenylphosphine (12.6g).At room temperature stir gained mixture and concentrated whole night.Resistates is divided between water and ETHYLE ACETATE to be dissolved.Use the ethyl acetate extraction water layer.Clean the merging organic phase with salt solution, via dried over mgso and filtration.Concentrating filtrate also passes through silica gel chromatography (with 5% eluent ethyl acetate in the methylene dichloride) purifying to produce title compound 6.2g. 1H?NMR(200MHz,CDC1 3)δ7.73(dd,J=8.2,0.8Hz,1H),7.30(br?s,1H),7.12(m,1H),4.38(m,3H),4.21(q,J=7.1Hz,2H),2.02(m,2H),1.82-1.25(m,13H)。
C.6-with 7-cyclohexyloxy-1,4-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance A-63d) prepare; Produce 7-cyclohexyloxy-1; 4-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester (compd A-74c1) (MS-(+)-ion M+1=360.16) and 6-cyclohexyloxy-1,4-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester (compd A-74c2) (MS-(+)-ion M+1=360.18).
D.1-bromo-7-cyclohexyloxy-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
In microwave reactor (ST) in 130 ℃ of heating 7-cyclohexyloxies-1,4-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester (compd A-74c1) (1.3g) and the mixture 15min of bromine phosphorus oxide (1.35g) in dry toluene (25ml).After cooling, concentrated reaction mixture.Handle resistates and at room temperature stir 20min with saturated sodium bicarbonate aqueous solution (100ml).Organic layer water, salt solution are cleaned, via dried over mgso, filtration and concentrated to produce title compound (1.2g).MS-(+)-ion M+1=422.12,424.12.
E.7-cyclohexyloxy-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
10%Pd/C (50% wet) (430mg) is added in the l-bromo-7-cyclohexyloxy-4-hydroxyl-mixture of isoquinoline-3-carboxylic acid butyl ester (936mg) in ETHYLE ACETATE (25ml) and then adds ammonium formiate (1.4g).Backflow gained mixture 4h.After the cooling, filter reaction mixture also concentrates.Through silica gel chromatography (the 3%-10% ETHYLE ACETATE in the methylene dichloride) purifying resistates to produce title compound (550mg).MS-(+)-ion, M+1=344.22.
F.2-(S)-[(7-cyclohexyloxy-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid
Mixture 40min in microwave reactor (ST) in 120 ℃ of heating 7-cyclohexyloxy-4-hydroxyl-isoquinoline-3-carboxylic acid butyl esters (80mg) and methyl alcohol (3.7ml) solution of L-L-Ala (207mg) at the 0.5M sodium methylate.Concentrated reaction mixture also is acidified to pH=4 with 2N HCl in water-soluble (30ml).Use ethyl acetate extraction.Water, salt solution clean and merge organic phase, via dried over mgso and filtration.Concentrating filtrate also produces title compound (52mg) through the silica gel chromatography purifying.MS-(+)-ion, M+1=359.18.
Instance A-75
2-(S)-{ [7-(4-fluoro-phenoxy)-4-hydroxyl-1-methyl-isoquinoline 99.9-3-carbonyl]-amino }-propionic acid
A.5-(4-fluoro-phenoxy)-isoindole-1, the 3-diketone
5-nitro-the isoindole-1 that under agitation refluxes, the 3-diketone (177g, 0.904mol), 4-fluoro-phenol (128g, 1.13mol), K 2CO 3(419g 3mol) and the mixture 3h of DMF (2l), under agitation injects water (12l) with this mixture then.Through isolated by vacuum filtration, water (8l) cleans and is with generation in 70 ℃ of dryings in a vacuum the title compound (43.2g) at pale brown toner end with formed throw out; 1HNMR (CDC1 3) δ=7.79 (d, 1H), 7.57 (br s, 1H), 7.01-7.29 (m, 6H).
B. [5-(4-fluoro-phenoxy)-1,3-dioxy-1,3-dihydro-isoindole-2-yl]-methyl acetate
5-(4-fluoro-the phenoxy)-isoindole-1 that under agitation refluxes, the 3-diketone (42.9g, 167mmol), the bromo-methyl acetate (21.1ml, 223mmol), K 2CO 3(62.3g, 446mmol) and Et 2The mixture 16h of CO (700ml) concentrates this mixture then in a vacuum.Water (150ml) is added in the resistates also with EtOAc (1 * 750ml, the slurries of 1 * 250ml) extraction gained.Via MgSO 4Dry merging organic phase also concentrates in a vacuum and is pale brown look solid title compound (49.7g) with generation; 1H NMR (CDCl 3) δ=7.80 (d, 1H), 7.01-7.30 (m, 6H), 4.41 (s, 2H), 3.76 (s, 3H).
C.7-(4-fluoro-phenoxy)-1,4-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester
Under agitation (7.2g 310mmol) is dissolved in the propyl carbinol (300ml) with sodium in 70 ℃.Then temperature is risen to 95-100 ℃ and under vigorous stirring, add [5-(4-fluoro-phenoxy)-1,3-dioxy-1,3-dihydro-isoindole-2-yl]-methyl acetate (49.4g 150mmol) is dissolved in solution in the hot propyl carbinol (300ml).Stir the other 90min of this mixture down and then under agitation make it be cooled to 60 ℃ at 95-100 ℃, add 2N HCl (160ml) then.This mixture of vigorous stirring 30min also then makes it be cooled to envrionment temperature.Subsequently, make this mixture vacuum filtration.Water thoroughly clean filter cake and under vacuum in 70 ℃ of dryings to produce light yellow solid.On silica gel, use CH through flash column chromatography 2Cl 2: EtOAc=98:2 comes purifying to produce title compound (14.4g, first part) as elutriant; 1H NMR (CDCl 3) δ=8.40 (br s, 1H), 8.14 (d, 1H), 7.80 (d, 1H), 7.42-7.48 (m, 1H), 7.04-7.14 (m, 4H), 4.39 (t, 2H), 1.70-1.85 (m, 2H), 1.37-1.55 (m, 2H), 0.99 (t, 3H).
D.1-bromo-7-(4-fluoro-phenoxy)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Gentle reflux 7-(4-fluoro-phenoxy)-1 under agitation, and 4-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester (14.33g, 38.6mmol), POBr 3(44.7g, 154.4mmol) with the mixture 75min of anhydrous methyl-cyanide (290ml), under agitation a small amount of then by part adding a NaHCO 3(100.8g, 1.2mol).Under agitation slowly add water (200ml) and this mixture of vigorous stirring 1h at ambient temperature subsequently, be concentrated into about 1/2 of its volume then in a vacuum.Also (1 * 400ml, 1 * 200ml) extracts this mixture with EtOAc then to add water (200ml).Via MgSO 4The dry organic phase that merges is also evaporated to produce pale brown look solid in a vacuum.This pale brown look solid is dissolved in CH 2Cl 2In and filter purifying through silica gel plug.Concentrate gained CH in the vacuum 2Cl 2Solution obtains title compound (11.4g); 1H NMR (CDCl 3) δ=11.89 (s, 1H), 8.36 (d, 1H), 7.57 (d, 1H), 7.44-7.50 (m, 1H), 7.08-7.16 (m, 4H), 4.47 (t, 2H), 1.78-1.93 (m, 2H), 1.38-1.58 (m, 2H), 0.99 (t, 3H).
E.7-(4-fluoro-phenoxy)-4-hydroxyl-1-methyl-isoquinoline-3-carboxylic acid butyl ester
Under agitation reflux 1-bromo-7-(4-fluoro-phenoxy)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (434mg, 1mmol), Pd (PPh 3) 4(116mg, 0.1mmol), trimethylboroxin (140 μ l, 1mmol), K 2CO 3(414mg, 3mmol) with 1, the mixture 2h of 4-dioxane (8ml).Concentrate this mixture subsequently in a vacuum.(10ml) is added in the resistates with water.Through adding 6N HCl this mixture of acidified aqueous solution and then extracting with EtOAc (40ml).Via MgSO 4Dry organic phase and evaporation in a vacuum.On silica gel, use hexane: EtOAc=94:6 to come the purifying resistates through flash column chromatography, produce the solid title compound (229mg) that is white in color as elutriant; MS-(+)-ion: M+1=370.1.
F.2-(S)-{ [7-(4-fluoro-phenoxy)-4-hydroxyl-1-methyl-isoquinoline 99.9-3-carbonyl]-amino }-propionic acid
In microwave oven under stirring 140 ℃ of heating 7-(4-fluoro-phenoxy)-4-hydroxyl-1-methyl-isoquinoline-3-carboxylic acid butyl ester (92mg; 0.25mmol), (S)-L-Ala (225mg; 2.5mmol) and the MeOH solution (5ml of 0.5N MeONa; 2.5mmol) mixture 20min, concentrate this mixture then in a vacuum.Water (10ml) is added in the resistates and (2 * 25ml) clean this mixture with EtOAc.Through the aqueous solution of the such purifying of interpolation 6N HCl acidifying and with EtOAc (1 * 25ml) extraction.Via MgSO 4Dry organic phase also concentrates in a vacuum and is pale brown look solid title compound (69mg) with generation; MS-(+)-ion: M+1=385.1.
Instance A-76
2-(S)-{ [7-(4-fluoro-phenoxy)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-propionic acid
A.7-(4-fluoro-phenoxy)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
At H 2Under environmental stress and temperature, stir l-bromo-7-(4-fluoro-phenoxy)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (4.34g under-the atmosphere; 10mmol; See instance A-75d), sodium acetate (984mg, 12mmol), Pd/C (2.0g, 10 weight %Pd; 50 weight % water), the mixture 2.5h of EtOAc (400ml) and MeOH (200ml), filter this mixture through plug of celite then.Clean zeyssatite with EtOAc (500ml).Concentrate in a vacuum and merge organic phase.Will half concentrated NaHCO 3Solution (50ml) is added in the resistates and uses CH 2Cl 2(1 * 200ml) extracts this mixture.Via MgSO 4Dry organic phase also concentrates the title compound (3.45g) to obtain being brown yellow oil in a vacuum; MS-(+)-ion: M+1=356.1.
B.2-(S)-{ [7-(4-fluoro-phenoxy)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-propionic acid
In microwave oven under stirring 130 ℃ of heating 7-(4-fluoro-phenoxy)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (154mg; 0.43mmol), (S)-L-Ala (225mg; 2.5mmol) and the MeOH solution (5ml of 0.5N MeONa; 2.5mmol) mixture 20min, concentrate this mixture then in a vacuum.Water (15ml) is added in the resistates and uses Et 2(3 * 30ml) clean this mixture to O.Through the aqueous solution of interpolation 6N HCl acidifying purifying and with EtOAc (1 * 30ml) extraction.Via MgSO 4Dry organic phase also concentrates in a vacuum and is pale brown look solid title compound (79mg) with generation; MS-(-)-ion: M-1=369.1.
Instance A-77
2-(S)-[(4-hydroxyl-1-methyl-7-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid
A.1-chloro-4-hydroxyl-6-phenoxy-isoquinoline-3-carboxylic acid butyl ester and 1-chloro-4-hydroxyl-7-phenoxy-isoquinoline-3-carboxylic acid butyl ester (regional isomerism mixture)
With l, 4-dihydroxyl-6-phenoxy-isoquinoline-3-carboxylic acid butyl ester and l, the regional isomerism mixture of 4-dihydroxyl-7-phenoxy-isoquinoline-3-carboxylic acid butyl ester (40.63g, 115mmol see instance A-65d) is added into POCl 3(300ml).Under agitation this mixture of gentle reflux 30min concentrates then in a vacuum.Resistates is dissolved among the EtOAc (800ml) and adds water (400ml).Then with NaHCO 3(about 100g) is added in the mixture of vigorous stirring by part on a small quantity.Stir this mixture 1h subsequently at ambient temperature, filter through Celite pad then.Separate organic phase, via MgSO 4Drying is also evaporated to produce pale brown look solid in a vacuum.This pale brown look solid is dissolved in CH 2Cl 2In and filter purifying through silica gel plug.Concentrate the CH of gained in the vacuum 2Cl 2Solution is to obtain being pale brown look solid title compound (15.51g); MS-(-)-ion M-1=370.2.
B.4-hydroxyl-1-methyl-7-phenoxy-isoquinoline-3-carboxylic acid butyl ester
(it is anhydrous 1 that 11.15g, regional isomerism mixture 30mmol) are added into, 4-dioxane (200ml), Pd (PPh with l-chloro-4-hydroxyl-6-phenoxy-isoquinoline-3-carboxylic acid butyl ester and l-chloro-4-hydroxyl-7-phenoxy-isoquinoline-3-carboxylic acid butyl ester 3) 4(3.47g, 3mmol), trimethylboroxin (4.22ml, 30mmol) and K 2CO 3(12.44g is in mixture 90mmol).At N 2-protection is down in stirring this mixture of refluxed 3h and then stirring 48h at ambient temperature.Subsequently, concentrate this mixture in a vacuum.Water (100ml) is added in the resistates and extracts this mixture with EtOAc (300ml).Via MgSO 4Dry organic phase and evaporation in a vacuum.On silica gel, use hexane: EtOAc=9 through flash column chromatography: 1 comes the purifying resistates as elutriant, produces the title compound (4.40g, first part) that is little yellow solid; MS-(+)-ion: M+1=352.1.
C.2-(S)-[(4-hydroxyl-1-methyl-7-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid
In microwave oven under stirring 120 ℃ of heating 4-hydroxyl-1-methyl-7-phenoxy-isoquinoline-3-carboxylic acid butyl ester (176mg; 0.5mmol), (S)-L-Ala (225mg; 2.5mmol) and the MeOH solution (5ml of 0.5N MeONa; 2.5mmol) mixture 20min, concentrate this mixture then in a vacuum.Water (15ml) is added in the resistates and uses Et 2(3 * 30ml) clean this mixture to O.6N HCl comes the aqueous solution of the such purifying of acidifying and (1 * 30ml) extracts with EtOAc through adding.Via MgSO 4Dry organic phase also concentrates in a vacuum and is pale brown look solid title compound (108mg) with generation; MS-(-)-ion: M-1=365.1.
Instance A-78
2-(S)-[(4-hydroxyl-1-methyl-7-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid
A) 1-bromo-4-hydroxyl-7-phenyl sulfenyl-isoquinoline-3-carboxylic acid
Stir 1 in the 600ml anhydrous acetonitrile, 4-dihydroxyl-7-phenyl sulfenyl-isoquinoline-3-carboxylic acid butyl ester (instance A-63d) compd A down refluxing) (29.0g) and bromine phosphorus oxide (67.5g) 4 hours.After cooling, concentrated reaction mixture also is added into saturated sodium bicarbonate solution and ETHYLE ACETATE in the resistates and stirs whole night.The throw out and the water that are collected in interlayer formation clean to produce title compound (10.2g).MS-(+)-ion M+1=376.0,378.1.
B) 1-bromo-4-hydroxyl-7-phenyl sulfenyl-isoquinoline-3-carboxylic acid methyl esters
Be suspended in the 500ml acetone 1-bromo-4-hydroxyl-7-phenyl sulfenyl-isoquinoline-3-carboxylic acid (10.0g), salt of wormwood (3.7g) and methyl-sulfate (3.4g) and stirred overnight under refluxing.Concentrated reaction mixture also divides resistates to dissolve between 1N hydrochloric acid and ETHYLE ACETATE.Via dried over mgso organic layer and filtration.Concentrating filtrate is to produce title compound (9.6g).MS-(+)-ion M+1=389.9,391.9.
C) 4-hydroxyl-1-methyl-7-phenyl sulfenyl-isoquinoline-3-carboxylic acid methyl esters
In microwave reactor (ST), heat 1,1-bromo-4-hydroxyl-7-phenyl sulfenyl-isoquinoline-3-carboxylic acid methyl esters (0.2g), tetrakis triphenylphosphine palladium (60mg), methyl boroxane (65mg) and salt of wormwood 10min in the 4-dioxane (4ml) in 140 ℃.After cooling, concentrated reaction mixture also divides molten between 1N hydrochloric acid and ETHYLE ACETATE.Via dried over mgso organic layer and filtration.Concentrating filtrate also passes through silica gel chromatography (with 2% eluent ethyl acetate in the methylene dichloride) and separates to produce title compound (47mg).MS-(+)-ion M+1=326.1.
D) 2-(S)-[(4-hydroxyl-1-methyl-7-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-propionic acid
Be similar to instance A-74f) prepare. 1H?NMR(200MHz,DMSO-d 6)δ13.26(br?s,1H),9.07(s,1H),8.61(s,1H),8.33(d,J=8.2Hz?1H),7.97(d,J=8.6Hz,1H),7.81(br?s,2H),7.52(br?s,3H),4.52(br?s,1H),2.91(s,3H),1.49(d,J=7.0Hz,3H)。
Instance A-79
2-(S)-{ [4-hydroxyl-7-(4-trifluoromethyl-phenoxy)-isoquinoline 99.9-3-carbonyl]-amino }-propionic acid
A) 4-(4-trifluoromethyl-phenoxy)-phthalonitrile
Be similar to instance A-66a) prepare. 1H?NMR(200MHz,CDC1 3)δ7.74(m,2H),7.47(d,J=8.6Hz,1H),7.25(m,3H),6.87(d,J=8.9Hz,1H)。
B) 4-(4-trifluoromethyl-phenoxy)-phthalic acid
Be similar to instance A-66b) prepare. 1H?NMR(200MHz,DMSO-d 6)δ8.24(d,J=9.0Hz,1H),7.75(m,3H),7.19(m,3H)。
C) [1,3-dioxy-5-(4-trifluoromethyl-phenoxy)-1,3-dihydro-isoindole-2-yl)-methyl acetate
Be similar to instance A-66c) prepare. 1H?NMR(200MHz,CDC1 3)δ7.86(d,J=8.5Hz,1H),7.67(d,J=8.2Hz,2H),7.40-7.13(m,4H),4.43(s,2H),3.769s,3H)。
D) 7-(4-trifluoromethyl-phenoxy)-1,4-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance A-66d) prepare.Separate two kinds of isomer to produce title compound through chromatography.MS-(+)-ion M+1=422.0.
E) 1-chloro-4-hydroxyl-7-(4-trifluoromethyl-phenoxy)-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance A-2c) prepare.MS-(-)-ion M-1=438.3.
F) 4-hydroxyl-7-(4-trifluoromethyl-phenoxy)-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance A-74e) prepare.MS-(+)-ion M+1=406.1.
G) 2-(S)-{ [4-hydroxyl-7-(4-trifluoromethyl-phenoxy)-isoquinoline 99.9-3-carbonyl]-amino }-propionic acid
Be similar to instance A-74f) prepare.MS-(+)-ion M+1=421.2.
Instance B-1
1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid (2-amino-ethyl)-acid amides; Three fluoro-acetates
A. (1,3-dioxy-1,3-dihydro-isoindole-2-yl)-butylacetate
The mixture of 160ml butanols, 20.0g (1,3-dioxy-1,3-dihydro-isoindole-2-yl)-acetate (94.6mmol) and the 2.0ml vitriol oil 24h that under agitation refluxes.Then by part adding a 5g sodium hydrogencarbonate, continue at room temperature to stir 5min and evaporating solvent in a vacuum.Resistates is divided in 100ml water and 100ml ETHYLE ACETATE to be dissolved.Clean organic phase with 100ml salt solution, also evaporate in a vacuum to produce little yellow oil with after coagulation via dried over sodium sulfate.Obtain the 24.02g title compound; MS-(+)-ion M+1=261.9.
B.1,4-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester
Under agitation 4.41g sodium (190mmol) is dissolved in the 250ml propyl carbinol.After sodium dissolves fully, make solution be cooled to envrionment temperature and under agitation add 24.0g (91.9mmol) (1,3-dioxy-1,3-dihydro-isoindole-2-yl)-butylacetate and be dissolved in the solution of 150ml butanols.With this solution at 30min internal heating to 100 ℃ and under this temperature, stir 1h.Then make this compound be cooled to envrionment temperature and also store 18h at ambient temperature.Then the pH value of compound is adjusted into 2 to 3 through under agitation adding the 2N aqueous hydrochloric acid.Continue to stir 30min, suction filtration solid ingredient then.Water thoroughly clean filter cake and under vacuum in 50 ℃ of dryings to produce white solid.Obtain the 17.75g title compound; MS-(+)-ion: M+1=262.1.
C.1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Stir 17.3g (66.2mmol) 1 at ambient temperature, the mixture 1h of 4-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester and 100ml phosphorus oxychloride also then under agitation slowly is heated to reflux temperature in 2h.This mixture of gentle reflux 30min under agitation.After being cooled to room temperature, evaporating excessive phosphorus oxychloride in a vacuum and resistates is dissolved in the 100ml ETHYLE ACETATE.This solution is under agitation injected the 300ml saturated sodium bicarbonate aqueous solution.Formed throw out removes through vacuum filtration.Separate organic phase and with the ethyl acetate extraction water of 3 * 100ml.Merge water via dried over sodium sulfate, filter through silicagel pad and also evaporate in a vacuum to produce brown oil with after coagulation.Obtain the 11.37g title compound; 1H NMR (CDC1 3): δ=11.91 (s, 1H), 8.41 (m, 1H), 8.29 (m, 1H), 7.83 (m, 2H), 4.49 (t, 2H), 1.84 (m, 2H), 1.48 (m, 2H), 0.99 (t, 3H).
D.1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid
The mixture 2h of 9.23g 1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (33mmol), 90ml 2.5N aqueous sodium hydroxide solution, water (20ml) and the ethanol (110ml) of under agitation refluxing.Then the pH value of mixture is adjusted into 2 through adding concentrated hydrochloric acid aqueous solution.In the interpolation process, through making the temperature of mixture remain on 20 ℃ with the ice bath cooling.Then continue to stir 1h, then through the isolated by vacuum filtration solid ingredient.Water clean filter cake and under vacuum in 85 ℃ of dryings to produce white powder.Obtain the 6.64g title compound; MS-(+)-ion: M+1=224.1.
E.{2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-ethyl }-t-butyl carbamate
96 μ l (0.55mmol) ethyl-di-isopropyl-amine under agitation are added in the mixture of 45mg (0.2mmol) 1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid, 76mg (0.2mmol) phosphofluoric acid benzotriazole-1-base-(two-dimethylamino-methylene radical)-oxygen (HBTU), 32 μ l (2-amino-ethyl)-t-butyl carbamate (0.2mmol) and 1ml methylene dichloride.Continue to stir at ambient temperature 5 days.Use hexane: ETHYLE ACETATE (8: 2) is as elutriant, through flash column chromatography on silica gel from reaction mixture separated product to produce pale brown coloring agent.Obtain the 8mg title compound; MS-(-)-ion: M-1=364.0.
F.1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid (2-amino-ethyl)-acid amides; Three fluoro-acetates
Stir the mixture 2h of 8mg (0.022mmol) { 2-[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-ethyl }-t-butyl carbamate and 2ml trifluoroacetic acid at ambient temperature.Then evaporate excessive trifluoroacetic acid in a vacuum, resistates is dissolved in also concentrates this solution in the absolute ethyl alcohol in a vacuum to produce pale brown look solid.Obtain the 8.5mg title compound; MS-(+)-ion: M+1=266.0.
Instance B-2
1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid (2-methoxyl group-ethyl)-acid amides
96 μ l (0.55mmol) ethyl-di-isopropyl-amine under agitation are added in the mixture of 45mg (0.2mmol) 1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid (from instance A-1d), 76mg (0.2mmol) phosphofluoric acid benzotriazole-1-base-(two-dimethylamino-methylene radical)-oxygen (HBTU), 18 μ l 2-methoxyl group-ethamine (0.2mmol) and 1ml methylene dichloride.Continue to stir at ambient temperature 12 days.Use hexane: ETHYLE ACETATE (9: 1) is as elutriant, through flash column chromatography on silica gel from reaction mixture separated product to produce white solid.Obtain the 8.8mg title compound; MS-(+)-ion: M+1=281.0.
Instance B-3
1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid (2-hydroxyl-ethyl)-acid amides
Be similar to instance 2, by from instance A-1d) 1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid and 2-amino-ethanol synthesize; MS-(-)-ion: M-1=265.2.
Instance B-4
1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid (2-dimethylamino-ethyl)-acid amides
At ambient temperature with 28mg (0.1mmol) from instance A-1c) 1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester, 116 μ l (1mmol) N, N-dimethyl--second-1, the mixture of the absolute ethyl alcohol of 2-diamines and 0.5ml stirs 18h.Then evaporating solvent in a vacuum is suspended in the 5ml water and resistates with the ethyl acetate extraction mixture of 2 * 35ml.Merging organic phase via dried over sodium sulfate also evaporates to produce little yellow solid in a vacuum.Obtain the 29mg title compound; MS-(+)-ion: M+1=294.1.
Instance B-5
1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid (2-acetylaminohydroxyphenylarsonic acid ethyl)-acid amides
Stir 56mg at ambient temperature from instance B-1c) the mixture 3 days of (0.2mmol) 1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester, 227mg (2mmol) N-(2-amino-ethyl)-ethanamide and 0.8ml absolute ethyl alcohol.Then evaporating solvent in a vacuum is suspended in resistates in the 3ml water, and through adding the 1N HCl aqueous solution pH value of this mixture is adjusted into 2 to 3.With this mixture of 2 * 25ml ethyl acetate extraction.Merging organic phase via dried over sodium sulfate also evaporates to produce little yellow solid in a vacuum.Obtain the 64mg title compound; MS-(+)-ion: M+1=308.1.
Instance B-6
1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline-3-carboxylic acid (2-hydroxyl-ethyl)-acid amides
Be similar to instance B-5, synthesize by l-chloro-4-hydroxyl-6-isopropoxy-isoquinoline-3-carboxylic acid butyl ester (can obtain) and 2-amino-ethanol according to people's such as Weidmann USP 6,093,730,10/1998; MS-(+)-ion: M+1=325.1.
Instance B-7
1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline-3-carboxylic acid (2-methoxyl group-ethyl)-acid amides
Be similar to instance B-5, synthesize by l-chloro-4-hydroxyl-6-isopropoxy-isoquinoline-3-carboxylic acid butyl ester (can obtain) and 2-methoxyl group-ethamine according to people's such as Weidmann USP 6,093,730,10/1998; MS-(+)-ion: M+1=339.0.
Instance B-8
1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline-3-carboxylic acid (2-amino-ethyl)-acid amides; Three fluoro-acetates
Be similar to instance B-5; (can be by l-chloro-4-hydroxyl-6-isopropoxy-isoquinoline-3-carboxylic acid butyl ester according to people's such as Weidmann USP 6,093,730; 10/1998 obtains) and (2-amino-ethyl)-t-butyl carbamate synthesize, be similar to instance B-1f then) come deprotection; MS-(+)-ion: M+1=324.1.
Instance B-9
1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline-3-carboxylic acid (2-dimethylamino-ethyl)-acid amides
Be similar to instance B-4, (can be by l-chloro-4-hydroxyl-6-isopropoxy-isoquinoline-3-carboxylic acid butyl ester according to people's such as Weidmann USP 6,093; 730,10/1998 obtain) and N, N-dimethyl--second-1; The 2-diamines synthesizes, and is similar to instance B-1f then) come deprotection; MS-(+)-ion: M+1=352.1.
Instance B-10
1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline-3-carboxylic acid (2-amino-ethyl)-acid amides; Three fluoro-acetates
Be similar to instance B-5; (can be by l-chloro-4-hydroxyl-7-isopropoxy-isoquinoline-3-carboxylic acid butyl ester according to people's such as Weidmann USP 6,093,730; 10/1998 obtains) and (2-amino-ethyl)-t-butyl carbamate synthesize, be similar to instance B-1f then) come deprotection; MS-(+)-ion: M+1=324.0.
Instance B-11
1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline-3-carboxylic acid (2-methoxyl group-ethyl)-acid amides
Be similar to instance B-5, synthesize by l-chloro-4-hydroxyl-7-isopropoxy-isoquinoline-3-carboxylic acid butyl ester (can obtain) and 2-methoxyl group-ethamine according to people's such as Weidmann USP 6,093,730,10/1998; MS-(-)-ion: M-1=337.1.
Instance B-12
1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline-3-carboxylic acid (2-dimethylamino-ethyl)-acid amides
Be similar to instance B-4, (can be by l-chloro-4-hydroxyl-7-isopropoxy-isoquinoline-3-carboxylic acid butyl ester according to people's such as Weidmann USP 6,093; 730,10/1998 obtain) and N, N-dimethyl--second-1; The 2-diamines synthesizes, and is similar to instance B-1f then) come deprotection; MS-(+)-ion: M+1=352.1.
Instance B-13
1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline-3-carboxylic acid (2-hydroxyl-ethyl)-acid amides
Be similar to instance B-5, synthesize by l-chloro-4-hydroxyl-7-isopropoxy-isoquinoline-3-carboxylic acid butyl ester (can obtain) and 2-amino-ethanol according to people's such as Weidmann USP 6,093,730,10/1998; MS-(-)-ion: M-1=323.2.
Instance C-1
1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline-3-carboxylic acid (2-hydroxyl-1-methylol-ethyl)-acid amides
With 0.035gm 1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline-3-carboxylic acid butyl ester and 0.088g 2-amino-the third-1, the 3-glycol is dissolved in the 1ml ethanol and refluxes this mixture 24h.Concentrated reaction mixture also is dissolved in resistates in the 10ml ETHYLE ACETATE.With 5ml1M HCl and water extraction ethyl acetate solution, dry (sodium sulfate) also concentrates to produce 0.042g white solid: MS-(+)-ion: 355.1.
Instance C-2
1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline-3-carboxylic acid (2-hydroxyl-1-methylol-ethyl)-acid amides
Be similar to instance C-1, by 1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline-3-carboxylic acid butyl ester and 2-amino-the third-1, the 3-glycol prepares: MS-(-)-ion: 353.2.
Instance C-3
1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid (2-hydroxyl-1-methylol-ethyl)-acid amides
Be similar to instance C-1, by 1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester and 2-amino-the third-1, the 3-glycol prepares: MS-(-)-ion: 295.2.
Instance D-1
[(4-hydroxyl-7-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
A) 4-phenyl sulfenyl-phthalic acid
5.06g 4-phenyl sulfenyl-phthalonitrile (21.4mmol), the 10ml 50%KOH aqueous solution and the 10ml methanol mixture of under agitation refluxing 3.5 days.Then also use the concentrated hydrochloric acid acidifying with this mixture of dilution of 100ml water.The suction filtration precipitated product, water thoroughly cleans also in a vacuum in 60 ℃ of dryings.Obtain the 5.75g title compound; MS-(-)-ion: M-1=273.0.
B) (1,3-dioxy-5-phenyl sulfenyl-1,3-dihydro-isoindole-2-yl)-acetate
In mortar, 5.62g 4-phenyl sulfenyl-phthalic acid (20.5mmol) and 1.55g glycocoll (20.5mmol) are thoroughly ground together.Then in oil bath with this mixture heating up to 210 ℃ to 220 ℃.Under this temperature, stir molten mass 15min, then it is cooled to envrionment temperature in a vacuum with scraper.Obtain the 6.30g title compound; MS-(-)-ion: M-1=311.8.
C) (1,3-dioxy-5-phenyl sulfenyl-1,3-dihydro-isoindole-2-yl)-methyl acetate
Under agitation with the mixture backflow 18h of 20ml methyl alcohol, 6.27g (1,3-dioxy-5-phenyl sulfenyl-1,3-dihydro-isoindole-2-yl)-acetate (20mmol) and the 0.3ml vitriol oil.Then add the dense sodium bicarbonate aqueous solution of 100ml also with this mixture of 100ml ethyl acetate extraction.Via MgSO 4Dry organic phase and evaporation in a vacuum.Obtain the 6.54g title compound; MS-(+)-ion: M+1=328.0.
D) 1,4-dihydroxyl-7-phenyl sulfenyl-isoquinoline-3-carboxylic acid butyl ester (A) and l, 4-dihydroxyl-6-phenyl sulfenyl-isoquinoline-3-carboxylic acid butyl ester (B)
Under agitation 0.92g sodium (40mmol) is dissolved in the 100ml propyl carbinol.Then temperature is increased to 95 ℃ to 100 ℃, adds 6.5g (1,3-dioxy-5-phenyl sulfenyl-1,3-dihydro-isoindole-2-yl)-methyl acetate (19.85mmol) and be dissolved in the hot soln in the 20ml propyl carbinol and under 95 ℃ to 100 ℃, continue to stir 1h.Evaporating solvent in a vacuum adds the 25ml 2N HCl aqueous solution and 100ml ETHYLE ACETATE and this mixture of vigorous stirring 1h, suction filtration then subsequently.Water thoroughly clean filter cake and under vacuum in 60 ℃ of dryings to produce the 4.43g yellow solid.On silica gel, use methylene dichloride through flash column chromatography: ETHYLE ACETATE (98: 2) wash-out separates this A of 4.4g and the mixture of B.Evaporate first fraction and obtain 1.99g A; 1H NMR (CDCl 3): δ=10.48 (bs, 1H), 8.39 (bs, 1H), 8.24 (d, 1H), 8.01 (d, 1H), 7.35-7.55 (m, 6H), 4.39 (t, 2H), 1.77 (m, 2H), 1.46 (m, 2H), 0.99 (t, 3H).Evaporate second fraction and obtain 2.26g B; 1H NMR (CDC1 3): δ=10.38 (bs, 1H), 8.32 (bs, 1H), 8.24 (d, 1H), 7.86 (d, 1H), 7.37-7.56 (m, 6H), 4.39 (t, 2H), 1.77 (m, 2H), 1.46 (m, 2H), 0.99 (t, 3H).
E) 1-bromo-4-hydroxyl-7-phenyl sulfenyl-isoquinoline-3-carboxylic acid butyl ester
With 1.108g 1,4-dihydroxyl-7-phenyl sulfenyl-isoquinoline-3-carboxylic acid butyl ester (3mmol) is added in the solution that 4.59g bromine phosphorus oxide (16mmol) is dissolved in the 25ml anhydrous acetonitrile and with this mixture gentle reflux 1h under agitation.Then add 5.04g sodium hydrogencarbonate (60mmol), dropwise add 8ml water then.After stirring 90min at ambient temperature, mixture is concentrated into the about 1/3rd of its volume in a vacuum, adds 40ml water and with this mixture of 30ml ethyl acetate extraction.This mixture of suction filtration.Separate organic phase, via MgSO 4Dry also through the silicagel pad filtration.Evaporate in a vacuum and produce the .885g title compound; 1H NMR (CDCl 3): δ=11.84 (s, 1H), 8.21 (d, 1H), 7.91 (d, 1H), 7.40-7.55 (m, 6H), 4.46 (t, 2H), 1.84 (m, 2H), 1.48 (m, 2H) .98 (t, 3H).
F) 4-hydroxyl-7-phenyl sulfenyl-isoquinoline-3-carboxylic acid butyl ester
432mg 1-bromo-4-hydroxyl-7-phenyl sulfenyl-isoquinoline-3-carboxylic acid butyl ester (1mmol), 63mg red phosphorus (2mmol), the aqueous solution (3mmol) of 0.4ml 57 weight %HI and the mixture 30min of 1ml Glacial acetic acid min. 99.5 under agitation reflux.Then,, use 0.2g NaHSO through the Celite pad suction filtration with 25ml ETHYLE ACETATE diluted reaction mixture 3The solution that is dissolved in 5ml water cleans and cleans twice with the dense sodium bicarbonate aqueous solution of 5ml.Via MgSO 4Dry organic phase and evaporation in a vacuum.On silica gel, use hexane through flash column chromatography: ETHYLE ACETATE (85: 15) wash-out comes the purifying resistates.Obtain the 123mg title compound; 1H NMR (CDC1 3): δ=11.85 (s, 1H), 8.60 (s, 1H), 8.23 (d, 1H), 7.38-7.63 (m, 7H), 4.49 (t, 2H), 1.87 (m, 2H), 1.47 (m, 2H) .98 (t, 3H).
G) [(4-hydroxyl-7-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
Under agitation with the mixture backflow 24h of methyl alcohol (3.2mmol) solution of 113mg 4-hydroxyl-7-phenyl sulfenyl-isoquinoline-3-carboxylic acid butyl ester (0.32mmol), 244mg glycocoll (3.2mmol) and 6.4ml 0.5N sodium methylate.Then evaporating solvent in a vacuum is dissolved in the 25ml water and resistates with the solution of 50ml ETHYLE ACETATE cleaning gained 2 times.Through adding concentrated hydrochloric acid the pH value of this solution is adjusted into about 3 also with the slurries of 25ml ethyl acetate extraction gained 2 times subsequently.Via MgSO 4The dry organic phase that merges is also evaporated in a vacuum.Obtain the 103mg title compound; 1H NMR (DMSO-d 6): δ=9.32 (t, 1H), 8.74 (s, 1H), 8.19 (d, 1H), 7.94 (d, 1H), 7.45-7.65 (m, 6H), 4.02 (d, 2H).
Instance D-2
[(4-hydroxyl-6-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
A) 1-bromo-4-hydroxyl-6-phenyl sulfenyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance D-1e), make to come from instance D-1d) the reaction of 1.447g compd B (4mmol) and bromine phosphorus oxide.On silica gel, come the purifying crude product through flash column chromatography with the methylene dichloride wash-out.Obtain the 0.985g title compound through evaporating first fraction; 1H NMR (CDCl 3): δ=11.77 (s, 1H), 8.08 (d, 1H), 8.05 (s, 1H), 7.41-7.56 (m, 6H), 4.46 (t, 2H), 1.85 (m, 2H), 1.48 (m, 2H), 0.98 (t, 3H).
B) 4-hydroxyl-6-phenyl sulfenyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance D-1f), make 540mg 1-bromo-4-hydroxyl-6-phenyl sulfenyl-isoquinoline-3-carboxylic acid butyl ester (1.25mmol) and red phosphorus and HI reaction.On silica gel, use hexane through flash column chromatography: ETHYLE ACETATE (85: 15) wash-out comes the purifying crude product.Obtain the 150mg title compound; 1H NMR (CDC1 3): δ=11.78 (s, 1H), 8.71 (d, 1H), 8.11 (t, 1H), 7.79 (d, 1H), 7.39-7.54 (m, 6H), 4.49 (t, 2H), 1.87 (m, 2H), 1.47 (m, 2H), 0.98 (t, 3H).
C) [(4-hydroxyl-6-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
Be similar to instance D-1g), make 127mg 4-hydroxyl-6-phenyl sulfenyl-isoquinoline-3-carboxylic acid butyl ester (0.36mmol) and glycocoll and sodium methylate reaction.Obtain the 118mg title compound; 1H NMR (DMSO-d 6): δ=9.33 (t, 1H), 8.80 (s, 1H), 8.11 (d, 1H), 7.79 (s, 1H), 7.49-7.65 (m, 6H), 4.01 (d, 2H).
Instance D-3
[(1-chloro-4-hydroxyl-7-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
A.1-chloro-4-hydroxyl-7-phenyl sulfenyl-isoquinoline-3-carboxylic acid butyl ester
Under agitation will be from instance D-1d) 554mg compd A (1.5mmol) and the mixture gentle reflux 30min of 5ml phosphorus oxychloride.Then evaporate the excess chlorine phosphorus oxide in a vacuum and resistates is dissolved in the 15ml acetonitrile.Add 2.94g sodium hydrogencarbonate (35mmol), dropwise add 4ml water then.After stirring 1h, mixture is concentrated into the about 1/3rd of its volume in a vacuum, adds 20ml water and with this mixture of 20ml ethyl acetate extraction 2 times.Via MgSO 4The dry organic phase that merges is also through the silicagel pad suction filtration.Evaporate in a vacuum and produce the 426mg title compound; 1H NMR (CDCl 3): δ=11.85 (s, 1H), 8.23 (d, 1H), 7.95 (d, 1H), 7.50-7.57 (m, 6H), 4.47 (t, 2H), 1.84 (m, 2H), 1.48 (m, 2H), 0.98 (t, 3H).
B) [(1-chloro-4-hydroxyl-7-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
Be similar to instance D-1g), make 194mg 1-chloro-4-hydroxyl-7-phenyl sulfenyl-isoquinoline-3-carboxylic acid butyl ester (0.5mmol) and glycocoll and sodium methylate reaction.Obtain the 168mg title compound; 1H NMR (DMSO-d 6): δ=9.17 (t, 1H), 8.24 (d, 1H), 7.51-7.79 (m, 7H), 4.00 (d, 2H).
Instance D-4
[(1-chloro-4-hydroxyl-6-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
A) 1-chloro-4-hydroxyl-6-phenyl sulfenyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance D-3a), make to come from instance D-1d) the reaction of 554mg compd B (1.5mmol) and phosphorus oxychloride.On silica gel, come the purifying crude product through flash column chromatography with the methylene dichloride wash-out.Obtain the 205mg title compound through evaporating first fraction; 1H NMR (CDCl 3): δ=11.78 (s, 1H), 8.08 (d, 1H), 8.06 (s, 1H), 7.41-7.56 (m, 6H), 4.46 (t, 2H), 1.85 (m, 2H), 1.48 (m, 2H), 0.98 (t, 3H).
B) [(1-chloro-4-hydroxyl-6-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
Be similar to instance D-1g), make 194mg 1-chloro-4-hydroxyl-6-phenyl sulfenyl-isoquinoline-3-carboxylic acid butyl ester (0.5mmol) and glycocoll and sodium methylate reaction.Obtain the 155mg title compound; 1H NMR (DMSO-d 6): δ=9.19 (t, 1H), 8.18 (d, 1H), 7.52-7.79 (m, 7H), 4.00 (d, 2H).
Instance D-5
[(1-bromo-4-hydroxyl-7-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
Be similar to instance D-1g), make to come from instance D-1e) 216mg 1-bromo-4-hydroxyl-7-phenyl sulfenyl-isoquinoline-3-carboxylic acid butyl ester (0.5mmol) and glycocoll react with sodium methylate.Obtain the 192mg title compound; 1H NMR (DMSO-d 6): δ=9.15 (t, 1H), 8.22 (d, 1H), 7.52-7.74 (m, 7H), 4.01 (d, 2H).
Instance D-6
[(1-bromo-4-hydroxyl-6-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
Be similar to instance D-1g), make to come from instance D-2a) 216mg 1-bromo-4-hydroxyl-6-phenyl sulfenyl-isoquinoline-3-carboxylic acid butyl ester (0.5mmol) and glycocoll react with sodium methylate.
Obtain the 194mg title compound; 1H NMR (DMSO-d 6): δ=9.17 (t, 1H), 8.12 (d, 1H), 7.51-7.78 (m, 7H), 4.00 (d, 2H).
Instance D-7
[(4-hydroxyl-7-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-acetate
A) 4-phenoxy-phthalic acid
Be similar to instance D-1a) synthetic by 4-phenoxy-phthalonitrile; MS-(-)-ion: M-1=256.9.
B) (1,3-dioxy-5-phenoxy-1,3-dihydro-isoindole-2-yl)-acetate
Be similar to instance D-1b) synthetic by 4-phenoxy-phthalic acid; MS-(+)-ion: M+1=297.9.
C) (1,3-dioxy-5-phenoxy-1,3-dihydro-isoindole-2-yl)-methyl acetate
Be similar to instance D-1c) by (1,3-dioxy-5-phenoxy-1,3-dihydro-isoindole-2-yl)-acetate synthetic (on silica gel, use hexane through flash column chromatography: ETHYLE ACETATE (1: 1) wash-out comes the purifying crude product); 1H NMR (CDC1 3): δ=7.83 (d, 1H), 7.05-7.46 (m, 7H), 4.41 (s, 2H), 3.76 (s, 3H).
D) 1,4-dihydroxyl-7-phenoxy-isoquinoline-3-carboxylic acid butyl ester (A) and l, 4-dihydroxyl-6-phenoxy-isoquinoline-3-carboxylic acid butyl ester (B)
It is synthetic by (1,3-dioxy-5-phenoxy-1,3-dihydro-isoindole-2-yl)-methyl acetate to be similar to instance D-1d}; A: 1H NMR (CDCl 3): δ=10.58 (bs, 1H), 8.37 (bs, 1H), 8.14 (d, 1H), 7.87 (d, 1H), 7.05-7.49 (m, 6H), 4.39 (t, 2H), 1.77 (m, 2H), 1.46 (m, 2H), 0.99 (t, 3H); B: δ=10.38 (bs, 1H), 8.38 (d, 1H), 8.28 (bs, 1H), 7.56 (d, 1H), 7.06-7.47 (m, 6H), 4.40 (t, 2H), 1.77 (m, 2H), 1.46 (m, 2H), 0.99 (t, 3H).
E) 1-bromo-4-hydroxyl-7-phenoxy-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance D-1e), by l, 4-dihydroxyl-7-phenoxy-isoquinoline-3-carboxylic acid butyl ester is synthetic; 1H NMR (CDCl 3): δ=11.89 (s, 1H), 8.35 (d, 1H), 7.63 (d, 1H), 7.08-7.52 (m, 6H), 4.47 (t, 2H), 1.84 (m, 2H), 1.48 (m, 2H), 0.99 (t, 3H).
F) 4-hydroxyl-7-phenoxy-isoquinoline-3-carboxylic acid butyl ester
Under hydrogen, stir the mixture 15h of 208mg 1-bromo-4-hydroxyl-7-phenoxy-isoquinoline-3-carboxylic acid butyl ester (0.5mmol), 49mg sodium acetate (0.6mmol), 50mg 10 weight % palladium charcoals, 10ml methyl alcohol and 5ml ETHYLE ACETATE in 1atm.Then through this mixture of Celite pad suction filtration and concentrated in a vacuum.Resistates is divided between 2ml half spissated bicarbonate aqueous solution and 8ml ETHYLE ACETATE to be dissolved.Via MgSO 4Dry organic phase.Evaporate in a vacuum and produce the 130mg title compound; 1H NMR (CDCl 3): δ=11.89 (bs, 1H), 8.61 (s, 1H), 8.36 (d, 1H), 7.10-7.53 (m, 7H), 4.49 (t, 2H), 1.87 (m, 2H), 1.47 (m, 2H), 0.98 (t, 3H).
G) [(4-hydroxyl-7-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-acetate
Be similar to instance D-1g), synthetic by 4-hydroxyl-7-phenoxy-isoquinoline-3-carboxylic acid butyl ester; 1H NMR (DMSO-d 6): δ=9.29 (t, 1H), 8.75 (s, 1H), 8.28 (d, 1H), 7.18-7.63 (m, 6H), 4.01 (d, 2H)
Perhaps, title compound is prepared as follows:
A ') 4-bromo-2-methyl-ethyl benzoate
The 25.3g 4-bromo-2-tolyl acid and the 5ml vitriol oil are added in the 425ml ethanol.This compound of heating is 3 days under reflux temperature.This solution is cooled to room temperature, is adjusted into neutral pH through adding sodium hydrogencarbonate, and under reduced pressure is concentrated into about 100ml volume.The mixture that volume is reduced divides molten between ETHYLE ACETATE and water, and cleans organic phase successively with saturated bicarbonate and salt brine solution.Via organic part of anhydrous sodium sulfate drying, and be concentrated into 28.2g clarified liq product; 1H NMR (200MHz, CDC1 3) δ 7.78-7.73 (d, J=8.2Hz, 1H), 7.38-7.32 (m, 2H), 4.40-4.28 (q, J=7Hz, 2H), 2.57 (s, 3H), 1.42-1.35 (t, J=7Hz, 3H).
B ') 2-methyl-4-phenoxy-ethyl benzoate
27.5g 4-bromo-2-methyl-ethyl benzoate is dissolved in the 120ml dry toluene.With 21.3g phenol, 73.6gCs 2CO 3, the active 4A molecular sieve of 551 μ L ETHYLE ACETATE, 22g and 5.68g 90% copper trifluoromethanesulfcomposite (I) benzene complex add so far in the solution.Place under the nitrogen atmosphere reaction and heating 48h under reflux temperature.The mixture of gained divided between water and ETHYLE ACETATE dissolve, and remove insoluble material through meticulous sintered glass filter filtering mixt.With 1.0N NaOH organic part is cleaned 3 times, clean 1 time with salt solution, via anhydrous sodium sulfate drying and be concentrated into 18.2g sundown liquid: 1H NMR (200MHz, CDCl 3) δ 7.93-7.88 (and dd, J=1.3,7.8Hz, 1H) 7.39-7.30 (m, 2H), 7.19-7.10 (tt, J=1.2; 7.4Hz, 1H), and 7.06-7.7.0 (m, 2H), 6.80-6.75 (m, 2H), 4.37-4.26 (q; J=7.0Hz, 2H), 2.56 (s, 3H), 1.40-1.33 (t, J=7.0Hz, 3H).
C ') 2-{ [(2,4-dimethoxy-benzyl)-oxyethyl group carbonyl methyl-amino]-methyl }-4-phenoxy-ethyl benzoate
Prepare N-(2, the 4-dimethoxy-benzyl) glycine ethyl ester (people such as Ananthan S, " pharmaceutical chemistry journal (J.Med.Chem.) (1993), 36 (4), the 479-490 page or leaf) according to the document program.13.0g 2-methyl-4-phenoxy-ethyl benzoate is dissolved in the 102mL tetracol phenixin.9.05g N-bromine succinic diamide and 492mg Lucidol are added so far in the solution.Under nitrogen atmosphere under reflux temperature heating this mixture 18h, be cooled to room temperature, and filter through silicagel pad and to remove all insoluble substances.The solution concentration of gained is slightly oily to 16.5g.
The above-mentioned thick oil of 2.0g is dissolved in the 10ml dry DMF.1.0g N-(2, the 4-dimethoxy-benzyl) glycine ethyl ester and 552mg salt of wormwood are added so far in the solution.Stirred reaction mixture 16h under nitrogen atmosphere.The gained mixture is injected 80ml water and divides 3 extractions with 50ml ETHYLE ACETATE.Clean organic part of merging successively with half saturated bicarbonate solution and salt solution.Organic part is evaporated to oily resistates and resuspending in 50ml ether and 10ml hexane.Solution is cooled to 0 ℃, and filtration removes micro-insoluble substance.The dioxane solution of 4M HCl slowly is added in the cold solution is settled out solid matter.Clean 2 times through solid collected by filtration salt and with cold diethyl ether.Then, this solid dissolves its dissolving through being divided between 150ml ETHYLE ACETATE and 100ml sodium bicarbonate aqueous solution.Separate organicly part, clean, via anhydrous sodium sulfate drying and concentrate 1.8g palm fibre yellow oil is provided with salt solution; MS (+) m/z508.13 (m+1).
D ') 2-(2,4-dimethoxy-benzyl)-4-hydroxyl-7-phenoxy-1,2-dihydro-isoquinoline-3-carboxylic acid ethyl ester
Under nitrogen atmosphere with 460mg 2-{ [(2,4-dimethoxy-benzyl)-oxyethyl group carbonyl methyl-amino]-methyl-4-phenoxy-ethyl benzoate is dissolved among the anhydrous THF of 16ml and with gained solution and is cooled to-78 ℃.Two (three silyls) Lithamides among the 1.95mL 1.0M THF are added so far in the solution.At-78 ℃ of reaction stirred 1.5h, and at room temperature stirred 4.5 hours.Gained solution is injected saturated aqueous ammonium chloride and with ethyl acetate extraction 3 times.Clean organic part with salt solution, via anhydrous sodium sulfate drying and be concentrated into yellow oil.With the 20-75% ETHYLE ACETATE gradient elution in the hexane, make this oil quick post of crossing on silica gel.Under reduced pressure fraction is concentrated into the 373mg yellow oil, it wants the enol and the ketone tautomers mixture of product through being determined as; MS (+) m/z 484.20 (m+23).
E ') 4-hydroxyl-7-phenoxy-isoquinoline-3-carboxylic acid ethyl ester
With 365mg 2-(2,4-dimethoxy-benzyl)-4-hydroxyl-7-phenoxy-1,2-dihydro-isoquinoline-3-carboxylic acid ethyl ester is dissolved in the 7.9ml methylene dichloride.92 μ L THIONYL CHLORIDE 97s are added so far in the solution.Reaction stirred 6.5h at room temperature, and then add 500 μ L ethanol and reaction stirred 10min in addition.This mixture is divided between ETHYLE ACETATE and sodium hydrogencarbonate to be dissolved.Clean organic part successively with 0.5M HCl, water, salt solution; Via anhydrous sodium sulfate drying, and be concentrated into the 468mg yellow oil.On silica gel, come this oil of purifying through flash chromatography, produce the 232mg crude product, the crystallization and produce 193mg creamy white solid from ether and hexane of this crude product with the 15-50% ETHYLE ACETATE gradient elution in the hexane; MS (+) m/z310.08 (m+1).
F) [(4-hydroxyl-7-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-acetate
Under the condition that is similar to instance D1-g, prepare title compound by 4-hydroxyl-7-phenoxy-isoquinoline-3-carboxylic acid ethyl ester.
Another alternative route of synthesis is to be used for the following 4-hydroxyl that provides-7-phenoxy-isoquinoline-3-carboxylic acid ethyl ester.
A ") 2-two brooethyls-4-phenoxy-ethyl benzoate
With the 40ml tetracol phenixin be added into be equipped with 2-methyl-4-phenoxy-ethyl benzoate (instance D-7b ') (3.05g), in the flask of N-bromine succinic diamide (4.65g) and benzyl peroxide (115mg).At refluxed under nitrogen gained mixture 16h.Leach insolubles and concentrated.Filter with this oil of the dilution of 10% ETHYLE ACETATE in the 50ml hexane and through silicagel pad, further continue flushing 2 times with same solvent mixture.To leach solution concentration and be buttery 2-two brooethyls-4-phenoxy-ethyl benzoate to produce 5g. 1H?NMR(200MHz,CDC1 3)δ8.07(s,1H),7.86(d,J=9Hz,1H),7.74(d,J=2.4Hz,1H),7.41(d,J=7.6,2H),7.21(m,1H),7.08(m,2H),6.86(dd,J=2.5,8.7,1H),4.37(q,J=7.0Hz,2H),1.40(t,J=7.0Hz,3H)。
B ") 2-formyl radical-4-phenoxy-ethyl benzoate
2-two brooethyls-4-phenoxy-ethyl benzoate (2.07g) is dissolved in THF (40ml) and the water (15ml).Add Silver Nitrate (2.56g).The gained mixture heating up to refluxing, is continued 5h.Leach throw out also with ETHYLE ACETATE diluting reaction thing.Separate organic layer and use the ethyl acetate extraction water layer once more.Clean the combined ethyl acetate layer and use dried over mgso with saturated sodium bicarbonate solution, salt solution.After concentrating, filter with the thick oil of the dilution of 20% ETHYLE ACETATE in the hexane (100ml) and through silicagel pad.Continue further flushing 2 times.To leach solution concentration and be the buttery title compound to produce 1.13g. 1H?NMR(200MHz,CDCl 3)δ10.62(s,1H),7.98(d,J=8.6Hz,1H),7.42-7.35(m,3H),7.20-7.14(m,2H),7.04(d,J=8.2,2H),4.41(q,J=7.0Hz,2H),1.41(t,J=7.0Hz,3H)。
C ") 2-(oxyethyl group carbonyl methyl-imino-methyl)-4-phenoxy-ethyl benzoate
Anhydrous methylene chloride (2ml) is added in the dry flask that glycine ethyl ester hydrochloride (62mg) is housed, adds triethylamine (124 μ L) then.Then add sal epsom (predrying under high vacuum with fan heater, 100mg), add methylene dichloride (1ml) solution of 2-formyl radical-4-phenoxy-ethyl benzoate (120mg) then.The flask that 2-formyl radical-4-phenoxy-ethyl benzoate is housed is further used the 0.5ml dichloromethane rinse.The mixture 15h of stirring at room gained under nitrogen.Filter this mixture and use dichloromethane rinse.Remove after the solvent, clean 2 times and drying with ether (15ml) diluting reaction thing and with salt solution.Filter and remove solvent, be the title compound that oily has good purity to produce 160mg. 1H?NMR(200MHz,CDC1 3)δ9.02(d,J=1.2,1H),7.94(d,J=8.6Hz,1H),7.63(d,J=2.4,1H),7.40-7.32(m,2H),7.20-7.11(m,1H),7.06-6.97(m,3H),4.41(s,2H),4.35(q,J=7.0Hz,2H),4.21(q,J=7.4Hz,2H),1.39(t,J=7.0Hz,3H),1.28(t,J=7.0Hz,3H)。
D ") 4-hydroxyl-7-phenoxy-isoquinoline-3-carboxylic acid ethyl ester
Make potassium tert.-butoxide (47mg) via Sprengel pump in about 90 ℃ of dryings more than 1 hour.Under nitrogen; (1.4ml) is added in the potassium tert.-butoxide with anhydrous tetrahydro furan; Then add tetrahydrofuran solution (1.6ml) solution of 2-(oxyethyl group carbonyl methyl-imino-methyl)-4-phenoxy-ethyl benzoate (60mg), and further add the 0.5ml THF.Mixture becomes redness by safran.After at room temperature stirring 2.5h, with mixture reflux again 2.5h and then water (5ml) make its quenching.Add ETHYLE ACETATE (30ml).Separate organic phase and clean also dry with salt solution.Remove solvent and be the title compound that oily has good purity to produce 26mg. 1H NMR (200MHz, CDC1 3): with instance D-7e ') identical.
Instance D-8
[(4-hydroxyl-6-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-acetate
A) 1-bromo-4-hydroxyl-6-phenoxy-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance D-1e), by coming from instance D-7d) dihydroxyl-6-phenoxy-isoquinoline-3-carboxylic acid butyl ester synthetic; 1H NMR (CDCl 3): δ=11.76 (s, 1H), 8.22 (d, 1H), 7.68 (d, 1H), 7.10-7.55 (m, 6H), 4.46 (t, 2H), 1.85 (m, 2H), 1.48 (m, 2H), 0.99 (t, 3H).
B) 4-hydroxyl-6-phenoxy-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance D-7f), synthetic by 1-bromo-4-hydroxyl-6-phenoxy-isoquinoline-3-carboxylic acid butyl ester; 1H NMR (CDCl 3): δ=11.76 (s, 1H), 8.74 (s, 1H), 7.93 (d, 1H), 7.69 (d, 1H), 7.10-7.52 (m, 6H), 4.49 (t, 2H), 1.87 (m, 2H), 1.47 (m, 2H), 0.98 (t, 3H).
C) [(4-hydroxyl-6-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-acetate
Be similar to instance D-1g), synthetic by 4-hydroxyl-6-phenoxy-isoquinoline-3-carboxylic acid butyl ester; 1H NMR (DMSO-d 6): δ=9.33 (t, 1H), 8.82 (s, 1H), 8.23 (d, 1H), 7.20-7.63 (m, 7H), 4.01 (d, 2H).
Instance D-9
[(1-chloro-4-hydroxyl-7-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-acetate
A) 1-chloro-4-hydroxyl-7-phenoxy-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance D-3a), by from instance D-7d) l, 4-dihydroxyl-7-phenoxy-isoquinoline-3-carboxylic acid butyl ester is synthetic; 1H NMR (CDCl 3): δ=11.90 (s, 1H), 8.37 (d, 1H), 7.10-7.64 (m, 7H), 4.47 (t, 2H), 1.84 (m, 2H), 1.48 (m, 2H), 0.99 (t, 3H).
B) [(1-chloro-4-hydroxyl-7-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-acetate
Be similar to instance D-1g), synthetic by 1-chloro-4-hydroxyl-7-phenoxy-isoquinoline-3-carboxylic acid butyl ester; 1H NMR (DMSO-d 6): δ=9.16 (t, 1H), 8.36 (d, 1H), 7.23-7.72 (m, 7H), 4.01 (d, 2H).
Instance D-10
[(1-chloro-4-hydroxyl-6-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-acetate
A) 1-chloro-4-hydroxyl-6-phenoxy-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance D-3a), by from instance D-7d) l, 4-dihydroxyl-7-phenoxy-isoquinoline-3-carboxylic acid butyl ester is synthetic; 1H NMR (CDCl 3): δ=11.77 (s, 1H), 8.25 (d, 1H), 7.69 (d, 1H), 7.10-7.55 (m, 6H), 4.47 (t, 2H), 1.85 (m, 2H), 1.48 (m, 2H), 0.98 (t, 3H).
B) [(1-chloro-4-hydroxyl-6-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-acetate
Be similar to instance D-1g), synthetic by 1-chloro-4-hydroxyl-6-phenoxy-isoquinoline-3-carboxylic acid butyl ester; 1H NMR (DMSO-d 6): δ=9.19 (t, 1H), 8.31 (d, 1H), 7.23-7.74 (m, 7H), 4.00 (d, 2H).
Instance D-11
[(1-bromo-4-hydroxyl-7-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-acetate
Be similar to instance D-1g), by from instance D-7e) 1-bromo-4-hydroxyl-7-phenoxy-isoquinoline-3-carboxylic acid butyl ester synthetic; MS-(+)-ion: M+1=417.0.
Instance D-12
[(1-bromo-4-hydroxyl-6-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-acetate
Be similar to instance D-1g), by from instance D-8a) 1-bromo-4-hydroxyl-7-phenoxy-isoquinoline-3-carboxylic acid butyl ester synthetic; MS-(-)-ion: M-1=414.9.
Instance D-13
{ [7-(2,6-dimethyl--phenoxy)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate
A) 4-(2,6-dimethyl--phenoxy)-phthalic acid
Be similar to instance D-1a) synthetic by 4-(2,6-dimethyl--phenoxy)-phthalonitrile; 1HNMR (CDC1 3): δ=7.89 (d, 1H), 7.19 (d, 1H), 7.08 (bs, 3H), 6.79 (m, lH), 2.10 (s, 6H).
B) [5-(2,6-dimethyl--phenoxy)-1,3-dioxy-1,3-dihydro-isoindole-2-yl]-methyl acetate
Be similar to instance D-1b) make 4-(2,6-dimethyl--phenoxy)-phthalic acid and glycine reactant.Then be similar to instance D-1c), make the reaction of crude product and methyl alcohol; 1H NMR (CDC1 3): δ=7.80 (d, 1H), 7.09-7.17 (m, 5H), 4.40 (s, 2H), 3.76 (s .2H), 2.11 (s, 6H).
C) 7-(2,6-dimethyl--phenoxy)-1,4-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester
Under agitation 0.79g sodium (34mmol) is dissolved in the 100ml propyl carbinol.Then temperature is increased to 95 ℃ to 100 ℃, disposable interpolation 5.70g [5-(2,6-dimethyl--phenoxy)-1,3-dioxy-1,3-dihydro-isoindole-2-yl]-methyl acetate (16.8mmol) also continues to stir 3h under 95 ℃ to 100 ℃.Evaporating solvent in a vacuum adds the 25ml 2N HCl aqueous solution and 100ml ETHYLE ACETATE and this mixture of vigorous stirring 30min, suction filtration then subsequently.Organic phase is separated from filtrate, via MgSO 4Dry also the evaporation in a vacuum to produce brown size and to use the methyl alcohol wet-milling.With the throw out suction filtration of gained and dried in vacuum to produce the little yellow solid of 870mg (A).Evaporate filtrate in a vacuum, be dissolved in the small amount of methanol and in refrigerator, store whole night.With the throw out suction filtration of gained and dried in vacuum to produce the little yellow solid of 246mg (B).Merge A and B and on silica gel, use methylene dichloride through flash column chromatography: ETHYLE ACETATE (98: 2) wash-out carries out purifying.Evaporate first fraction and obtain the 762mg title compound; 1H NMR (CDC1 3): δ=8.31 (bs, 1H), 8.12 (d, 1H), 7.60 (d, 1H), 7.35 (m, 1H), 7.09 (bs, 3H), 4.39 (t, 2H), 2.11 (s, 6H), 1.77 (m, 2H), 1.44 (m, 2H), 0.99 (t, 3H).
D) 1-bromo-7-(2,6-dimethyl--phenoxy)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance D-1e), by 7-(2,6-dimethyl--phenoxy)-1,4-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester is synthetic; 1H NMR (CDCl 3): δ=11.88 (s, 1H), 8.33 (m, 1H), 7.35-7.40 (m, 2H), 7.13-7.16 (m, 3H), 4.46 (t, 2H), 2.14 (s, 6H), 1.83 (m, 2H), 1.48 (m, 2H), 0.98 (t, 3H).
E) 7-(2,6-dimethyl--phenoxy)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance D-7f), synthetic by 1-bromo-7-(2,6-dimethyl--phenoxy)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester; 1H NMR (CDCl 3): δ=11.87 (s, 1H), 8.35 (s, 1H), 8.36 (d, 1H), 7.47 (dd, 1H), 7.14 (m, 2H), 6.87 (d, 1H), 4.48 (t, 2H), 2.14 (s, 6H), 1.87 (m, 2H), 1.47 (m, 2H), 0.98 (t, 3H).
F) { [7-(2,6-dimethyl--phenoxy)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate
Be similar to instance D-1g), synthetic by 7-(2,6-dimethyl--phenoxy)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester; MS-(+)-ion: M+1=367.1.
Instance D-14
{ [1-chloro-7-(2,6-dimethyl--phenoxy)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate
A) 1-chloro-7-(2,6-dimethyl--phenoxy)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance D-3a), by from instance D-13c) 7-(2,6-dimethyl--phenoxy)-1,4-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester is synthetic; 1H NMR (CDCl 3): δ=11.89 (s, 1H), 8.35 (d, 1H), 7.34-7.43 (m, 2H), 7.13-7.14 (m, 3H), 4.47 (t, 2H), 2.14 (s, 6H), 1.85 (m, 2H), 1.48 (m, 2H), 0.99 (t, 3H).
B) { [1-chloro-7-(2,6-dimethyl--phenoxy)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate
Be similar to instance D-1g), synthetic by 1-chloro-7-(2,6-dimethyl--phenoxy)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester; MS-(-)-ion: M-1=398.9.
Instance D-15
{ [1-bromo-7-(2,6-dimethyl--phenoxy)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate
Be similar to instance D-1g), by from instance D-13d) 1-bromo-7-(2,6-dimethyl--phenoxy)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester synthetic; MS-(-)-ion: M-1=442.9.
Instance D-16
[(1-bromo-7-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
A) (5-chloro-1,3-dioxy-1,3-dihydro-isoindole-2-yl)-acetate
Be similar to instance D-1b) come synthetic (use 5-chloro-isobenzofuran-1, the 3-diketone replaces corresponding phthalic acid as starting substance); 1H NMR (DMSO-d 6/ D 2O): δ=8.01 (s, 1H), 7.93 (s, 2H), 4.32 (s, 2H).
B) (5-chloro-1,3-dioxy-1,3-dihydro-isoindole-2-yl)-methyl acetate
Be similar to instance D-1c) synthetic by (5-chloro-1,3-dioxy-1,3-dihydro-isoindole-2-yl)-acetate; 1H NMR (CDC1 3): δ=7.67-7.86 (m, 3H), 4.43 (s, 2H), 3.76 (s, 3H).
C) the 7-chloro-1,4-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester (A) and 6-chloro-1,4-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester (B)
Be similar to instance D-1d), by (5-chloro-1,3-dioxy-1,3-dihydro-isoindole-2-yl)-methyl acetate synthetic (pure B through after chromatography from chloroform recrystallize obtain); A: 1H NMR (CDCl 3): δ=8.46 (bs, 1H), 8.41 (d, 1H), 8.10 (d, 1H), 7.73 (dd, 1H), 4.41 (t, 2H), 1.77 (m, 2H), 1.46 (m, 2H), 1.00 (t, 3H); B: 1H NMR (CDCl 3): δ=8.34-8.38 (m, 2H), 8.12 (d, 1H), 7.64 (dd, 1H), 4.42 (t, 2H), 1.77 (m, 2H), 1.46 (m, 2H), 1.00 (t, 3H).
D) 1-bromo-7-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance D-1e), by 7-chloro-1,4-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester is synthetic; 1H NMR (CDCl 3): δ=11.92 (s, 1H), 8.34 (d, 1H), 8.25 (d, 1H), 7.75 (dd, 1H), 4.49 (t, 2H), 1.86 (m, 2H), 1.48 (m, 2H), 1.00 (t, 3H).
E) [(1-bromo-7-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
Be similar to instance D-1g), synthetic by 1-bromo-7-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester; MS-(-)-ion: M-1=356.8.
Instance D-17
[(1-bromo-6-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
A) 1-bromo-6-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance D-1e), by from instance D-16c) 6-chloro-1,4-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester is synthetic; 1H NMR (CDCl 3): δ=11.88 (s, 1H), 8.37 (d, 1H), 8.19 (d, 1H), 7.75 (dd, 1H), 4.49 (t, 2H), 1.86 (m, 2H), 1.48 (m, 2H), 0.99 (t, 3H).
B) [(1-bromo-6-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
Be similar to instance D-1g), synthetic by 1-bromo-6-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester; MS-(-)-ion: M-1=356.9.
Instance D-18
[(1-bromo-4-hydroxyl-7-trifluoromethyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
A) (1,3-dioxy-5-Trifluoromethyl-1,3-dihydro-isoindole-2-yl)-methyl acetate
Be similar to instance D-1b) make 4-trifluoromethyl-phthalic acid and glycine reactant.Then be similar to instance D-1c), make the reaction of crude product and methyl alcohol; 1H NMR (CDC1 3): δ=8.14 (s, 1H), 8.02 (m, 2H), 4.48 (s, 2H), 3.78 (s, 3H).
B) 1,4-dihydroxyl-7-trifluoromethyl-isoquinoline-3-carboxylic acid butyl ester (A) and 1,4-dihydroxyl-6-trifluoromethyl-isoquinoline-3-carboxylic acid butyl ester (B)
Be similar to instance D-1d) synthetic by (1,3-dioxy-5-Trifluoromethyl-1,3-dihydro-isoindole-2-yl)-methyl acetate; A: 1H NMR (CDCl 3): δ=10.47 (bs, 1H), 8.76 (bs, 1H), 8.72 (d, 1H), 8.29 (m, 1H), 7.99 (m, 1H), 4.45 (t, 2H), 1.77 (m, 2H), 1.46 (m, 2H), 1.00 (t, 3H); B: 1H NMR (CDCl 3): δ=10.48 (bs, 1H), 8.44-8.57 (m, 3H), 7.91 (d, 1H), 4.44 (t, 2H), 1.77 (m, 2H), 1.46 (m, 2H), 1.01 (t, 3H).
C) 1-bromo-4-hydroxyl-7-trifluoromethyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance D-1e), by 1,4-dihydroxyl-7-trifluoromethyl-isoquinoline-3-carboxylic acid butyl ester is synthetic; 1H NMR (CDCl 3): δ 11.96 (s, 1H), 8.52-8.56 (m, 2H), 7.99 (dd, 1H), 4.51 (t, 2H), 1.86 (m, 2H), 1.48 (m, 2H), 1.00 (t, 3H).
D) [(1-bromo-4-hydroxyl-7-trifluoromethyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
Be similar to instance D-1g), synthetic by 1-bromo-4-hydroxyl-7-trifluoromethyl-isoquinoline-3-carboxylic acid butyl ester; MS-(-)-ion: M-1=391.0.
Instance D-19
[(1-bromo-4-hydroxyl-6-trifluoromethyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
A) 1-bromo-4-hydroxyl-6-trifluoromethyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance D-1e), by from instance D-18b) 1,4-dihydroxyl-6-trifluoromethyl-isoquinoline-3-carboxylic acid butyl ester is synthetic; MS-(-)-ion: M-1=390.3.
B) [(1-bromo-4-hydroxyl-6-trifluoromethyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
Be similar to instance D-1g), synthetic by 1-bromo-4-hydroxyl-6-trifluoromethyl-isoquinoline-3-carboxylic acid butyl ester; MS-(-)-ion: M-1=390.9.
Instance D-20
[(4-hydroxyl-1-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-acetate
A) (1,3-dioxy-1,3-dihydro-isoindole-2-yl)-methyl acetate
Be similar to instance D-1c) synthetic by (1,3-dioxy-1,3-dihydro-isoindole-2-yl)-acetate; 1H NMR (CDC1 3): δ=7.84-7.91 (m, 2H), 7.71-7.77 (m, 2H), 4.45 (s, 2H), 3.77 (s, 3H).
B.1,4-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance D-1d), by (1,3-dioxy-1,3-dihydro-isoindole-2-yl)-methyl acetate synthetic (before adding hydrochloric acid not evaporating solvent, do not add ETHYLE ACETATE); 1HNMR (DMSO-d 6): δ=10.66 (bs, 1H), 10.55 (bs, 1H), 8.27 (d, 1H), 8.08 (d, 1H), 7.72-7.92 (m, 2H), 4.33 (t, 2H), 1.74 (m, 2H), 1.44 (m, 2H), 0.93 (t, 3H).
C.1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance D-3a), by l, 4-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester is synthetic; 1H NMR (CDCl 3): δ=11.91 (s, 1H), 8.41 (m, 1H), 8.29 (m, 1H), 7.83 (m, 2H), 4.49 (t, 2H), 1.84 (m, 2H), 1.48 (m, 2H), 0.99 (t, 3H).
D) 4-hydroxyl-1-phenoxy-isoquinoline-3-carboxylic acid butyl ester
The mixture of 1.399g 1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (5mmol) and 2.86g phenol is heated 24h at 145 ℃ to 150 ℃.After being cooled to envrionment temperature, mixture is suspended in the 50ml 2N NaOH aqueous solution also with this mixture of 4 * 25ml ethyl acetate extraction.Clean the merging organic phase with 3 * 25ml 2N NaOH aqueous solution, 50ml salt solution, via MgSO 4Dry also evaporation in a vacuum.On silica gel, use hexane through flash column chromatography: ETHYLE ACETATE (9:1) and (95:5) wash-out come the purifying resistates.Obtain the 0.650g title compound; 1H NMR (CDC1 3): δ=11.52 (s, 1H), 8.32-8.39 (m, 2H), 7.72-7.86 (m, 2H), 7.13-7.42 (m, 5H), 4.31 (t, 2H), 1.69 (m, 2H), 1.37 (m, 2H), 0.93 (t, 3H).
E) [(4-hydroxyl-1-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-acetate
Be similar to instance D-1g), synthetic by 4-hydroxyl-1-phenoxy-isoquinoline-3-carboxylic acid butyl ester; MS-(+)-ion: M+1=339.1.
Instance D-21
[(1,7-two bromo-4-hydroxyl-isoquinoline 99.9-3-carbonyls)-amino]-acetate
A) (5-bromo-1,3-dioxy-1,3-dihydro-isoindole-2-yl)-ETHYLE ACETATE
With the bromine phthalic imidine (35g, 155mmol) and bromoethyl acetate (bromoethylacetate) (31g 186mmol) is dissolved in the 700ml acetone.(64.2g is 465mmol) and at the suspension-s 18h of stirring gained down that refluxes to add salt of wormwood.After the cooling, filter this mixture.The evaporation filtrate is to produce 48.12g (154mmol) solid product. 1HNMR(200MHz,CDCl 3)δ8.00(s,1H),7.89(d,J=7.8Hz,1H),7.73(d,J=7.8Hz,1H),4.41(s,2H),4.21(q,J=7.0Hz,2H),1.28(t,J=7.0Hz,3H)。
B) 6-and 7-bromo-1,4-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester
(45-50 ℃) is dissolved in sodium (10.45g) in the 460ml propyl carbinol under heating.(68g 218mmol) is dissolved in the 460ml propyl carbinol (being heated to evenly), and then is added in the sodium solution with above-mentioned ester.At 75 ℃ of following mechanical stirring combined mixture 1h.Remove mixture and stirred overnight at room temperature through heating.Use 2N HCl that solution is acidified to pH and be about 3.The product that then is two kinds of isomer mixtures through vacuum filtration collecting precipitation thing and water with generation 59.4g (175mmol) with washed with methanol.
C) the 7-bromo-1,4-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester
Carry out the flash chromatography on silica gel method, with the above-mentioned heterogeneous mixture of 10g with 10% eluent ethyl acetate in the methylene dichloride to produce the 3g solid product that is white in color.MS-(+)-ion: M+1=342.02,340.02.
D) 1,7-two bromo-4-hydroxyl-isoquinoline-3-carboxylic acid butyl esters
(2.4g 7.1mmol) is dissolved in the 150ml anhydrous acetonitrile with above-mentioned ester.Interpolation bromine phosphorus oxide (14.1g, 49.4mmol).3h stirs the mixture under refluxing.After the cooling, concentrated reaction mixture also places ETHYLE ACETATE with resistates.Under effectively stirring, ethyl acetate mixture is injected saturated sodium bicarbonate solution.Separate two phases.Merge organic layer, filtration and concentrated via dried over mgso to produce 2g product (5.0mmol).MS-(+)-ion: M+1=403.90.
E} [(1,7-two bromo-4-hydroxyl-isoquinoline 99.9-3-carbonyls)-amino]-acetate
(0.2g 0.5mmol) is dissolved in the 5ml ethanol with above-mentioned ester.With glycocoll (0.24g, 9.9mmol) and sodium ethylate (0.34g 5mmol) adds so far in the solution.
Under refluxing, stirred the mixture 3 days.Evaporating mixture.Resistates is dissolved in the water and cleans with ETHYLE ACETATE.Use 1N HCl acidified aqueous solution water layer to pH=3-4, then use ethyl acetate extraction.Via the dried over mgso organic layer, filter and concentrate to produce the 0.17g solid product that is white in color. 1H?NMR(200MHz,DMSO-d6)δ9.26(t,J=6.2Hz,1H),8.32(d,J=1.6Hz,1H),8.23(d,J=9.0Hz,1H),8.11(dd,J=9.0,1.6Hz,1H),4.02(d,J=6.2Hz,2H)。
Instance D-22
[(7-bromo-1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
A) 7-bromo-1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
With 170mg (0.5mmol) 7-bromo-1,4-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester (from instance D-21c) is dissolved in the 2ml anhydrous acetonitrile.(536mg is 3.5mmol) and at the mixture 4h of stirring gained down that refluxes to add phosphorus oxychloride.After the cooling, concentrate this mixture and resistates is inserted in the ETHYLE ACETATE.Ethyl acetate mixture is injected saturated sodium bicarbonate solution, effectively stir 1h simultaneously.Separate two phases.Use the ethyl acetate extraction water layer.Merge organic layer, filtration and concentrated via dried over mgso.Come the purifying crude product to produce the 78mg solid product that is white in color through silica gel chromatography with the methylene dichloride wash-out.MS-(+)-ion: M+1=359.96,357.98.
B) [(7-bromo-1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
Be similar to instance D-21e), make 75mg (0.21mmol) above-mentioned ester and glycocoll (341mg, 4.18mmol) and sodium ethylate (143mg, 2.09mmol) reaction.Obtain the 58mg product. 1HNMR(200MHz,CD 3OD)δ8.44(d,J=1.6Hz,1H),8.28(d,J=9.0Hz,1H),8.00(dd,J=9.0,1.6Hz,1H),4.17(s,2H)。
Instance D-23
[(6-bromo-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
A) 6-bromo-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
With 2.58g (6.40mmol) 6-and 7-bromo-1,4-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester mixture (from instance D-21b) is dissolved in the 30ml Glacial acetic acid min. 99.5.Add palladium (10% in the activated carbon) slurries in the 10ml Glacial acetic acid min. 99.5.2h stirs the mixture under nitrogen atmosphere (storage pressure).Leach catalyzer and use dichloromethane rinse through Celite pad.Concentrating filtrate and with resistates wet-milling in methylene dichloride.Through filtering and using the silica gel chromatography of (3/1) hexane/ethyl acetate to collect insoluble solids to produce the 192mg product.MS-(-)-ion: M-1=324.11,322.13.
B) [(6-bromo-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
Be similar to instance D-21e), make 178mg (0.55mmol) above-mentioned ester and glycocoll (1.23g, 16.43mmol) and sodium ethylate (746mg, 10.96mmol) reaction.The product that is further obtained with the wet-milling of 30ml methyl alcohol produces the 58mg product. 1H?NMR(200MHz,CD 3OD)δ8.72(s,1H),8.46(s,1H),7.98(d,J=8.8Hz),7.86(d,J=8.8Hz,lH),4.14(s,2H)。
Instance D-24
[(1-bromo-7-fluoro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
A) (5-fluoro-1,3-dioxy-1,3-dihydro-isoindole-2-yl)-methyl acetate
With 5-fluoro-isobenzofuran-1, the 3-diketone (3.68g, 22.15mmol) and glycocoll (1.66g, solid mixture 22.15mmol) stirs down 5min at 200-220 ℃.After the cooling, it is dissolved in the 25ml acetone.Add methyl-sulfate (4.19g, 33.23mmol) and salt of wormwood (4.59g, 33.23mmol).Under refluxing, stir this mixture 2h.After the cooling, it is diluted with 100ml ETHYLE ACETATE.Leach insolubles and concentrating filtrate.Place 200ml ETHYLE ACETATE and water and salt solution to clean resistates.Via dried over mgso ethyl acetate layer, filtration and concentrated to produce the 5.1g product. 1H?NMR(200MHz,CDC1 3)δ7.88(dd,J=8.2,4.3Hz,1H),7.54(dd,J=6.8,2.2Hz,1H),7.40(m,1H),4.44(s,2H),3.77(s,3H)。
B) the 7-fluoro-1,4-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester (A) and 6-fluoro-1,4-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester (B)
Be similar to instance D-21b, under 95-100 ℃, the above-mentioned ester of 3.0g (12.66mmol) reset 2h, to produce the product that 2.5g is isomer mixture.Come the purifying heterogeneous mixture through silica gel chromatography with the 5-20% eluent ethyl acetate in the methylene dichloride.Concentrate first fraction and from 60ml ethanol recrystallize to produce 268mg solid product (A).Concentrate second fraction to produce 313mg solid product (B).For product A: MS-(-)-ion: M-1=278.02; For product B: MS-(-)-ion: M-1=278.03.
The difference of can be on the silica gel tlc plate measuring isomer A and B: A:R with 10% ETHYLE ACETATE in the methylene dichloride fValue is about 0.79; B:R fValue is about 0.53.
C) 1-bromo-7-fluoro-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Being similar to instance D-21d (using 10% methyl alcohol in the methylene dichloride to replace ETHYLE ACETATE) comes the above-mentioned ester of bromination 250mg (0.90mmol) (A) to produce the 156mg solid product.MS-(+)-ion: M+1=344.00,341.99.
D) [(1-bromo-7-fluoro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
Be similar to instance D-21e, make above-mentioned ester of 60mg (0.18mmol) and glycine reactant (reaction times is 48h).Use 10% methyl alcohol in the methylene dichloride to extract this product.Via dried over mgso organic layer, filtration and concentrated to produce the 50mg product.MS-(-)-ion: M-1=343.02,340.92; 1H NMR (200MHz, acetone-d 6) δ 13.56 (s, 1H), 8.81 (br s, 1H), 8.43 (dd, J=9.0,5.4Hz, 1H), 7.79 (m, 2H), 4.29 (d, J=6.2Hz, 2H).
Instance D-25
[(7-fluoro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
The above-mentioned carboxylic acid of 42mg (0.12mmol) is dissolved in 5ml (4/1) methanol.Add yellow soda ash (13mg, 0.12mmol) with palladium (wetting 10% dry matter on the activated carbon) (40mg).2h stirs the mixture under nitrogen atmosphere (storage pressure).Leaching catalyzer through Celite pad also also then washes with 2ml water with 10ml (4/1) methanol.Concentrating filtrate is to remove most of methyl alcohol and to be acidified to pH=3-4 through 1N HCl.Through filtration collecting precipitation thing and dry to produce the 14mg product under high vacuum.MS-(-)-ion: M-1=262.99; 1H NMR (200MHz, CD 3OD) δ 8.69 (s, 1H), 8.38 (dd, J=9.0,5.5Hz, 1H), 7.24 (dd, J=9.3,2.4Hz, 1H), 7.60 (m, 1H), 4.14 (s, 2H).
Instance D-26
[(1-chloro-7-fluoro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
A) 1-chloro-7-fluoro-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
With 135mg (0.48mmol) 7-fluoro-1,4-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester (from the product A of instance D-24b) is dissolved in the 3ml anhydrous acetonitrile.The interpolation phosphorus oxychloride (1.24g, 8.07mmol).Under refluxing, stir this mixture 6h.After the cooling, it is concentrated and is suspended in the 10ml saturated sodium bicarbonate aqueous solution.Stir 1h also with 5% methanol extraction in the methylene dichloride.Clean organic layer with salt solution, via dried over mgso, filtration and concentrated.Come the thick resistates of purifying to produce the 58mg product through silica gel chromatography with the methylene dichloride wash-out.MS-(-)-ion: M-1=296.12.
B. [(1-chloro-7-fluoro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
Be similar to instance D-21e, make above-mentioned ester of 55mg (0.19mmol) and glycine reactant.After the acidifying, with 10% methanol extraction in the methylene dichloride.Clean organic layer with salt solution, via dried over mgso, filtration and concentrated.Through the preparation TLC purifying resistates on 10% methyl alcohol in methylene dichloride to produce the 6mg product. 1H NMR (200MHz, the δ 13.59 of acetone-d6) (s, 1H), 8.90 (br s, 1H), 8.47 (dd, J=9.0,5.1Hz, 1H), 7.94 (dd, J=9.7,2.4Hz, 1H), 7.81 (m, 1H), 4.28 (d, J=6.2Hz, 2H).
Instance D-27
[(chloro-4-hydroxyl-benzo [g] isoquinoline 99.9-3-carbonyl)-amino]-acetate
A) (1,3-dioxy-1,3-dihydro-benzo [f] isoindole-2-yl)-ETHYLE ACETATE
Be similar to instance D-21a, make 2g (10.1mmol) benzo [f] isoindole-1,3-diketone and METHYL BROMOACETATE reaction.Between ETHYLE ACETATE and water, divide and dissolve and the acquisition crude product.Clean organic layer with salt solution, via dried over mgso, filtration and evaporation are to produce 2.68g (9.5mmol) product. 1H?NMR(200MHz,CDC1 3)δ8.36(s,2H),8.05(m,2H),7.68(m,2H),4.49(s,2H),4.22(q,J=7.0Hz,2H),1.29(t,7.0Hz,3H)。
B) 1,4-dihydroxyl-benzo [g] isoquinoline-3-carboxylic acid butyl ester
Be similar to instance D-21b, the above-mentioned isoindole ester of 2.6g (9.2mmol) is reset to produce 1.23g (3.9mmol) product. 1HNMR(200MHz,CDC1 3)δ10.73(br?s,1H),9.00(s,1H),8.68(s,1H),8.24(br?s,1H),8.06(m,2H),7.68(m,2H),4.24(t,J=6.6Hz,2H),1.80(m,2H),1.47(m,2H),1.00(t,J=7.4Hz,3H)。
C) 1-chloro-4-hydroxyl-benzo [g] isoquinoline-3-carboxylic acid butyl ester
Be similar to instance D-22a but do not use acetonitrile to make the reaction of the above-mentioned ester of 1g (3.2mmol) and 5ml phosphorus oxychloride to produce 0.88g (2.7mmol) product as cosolvent. 1HNMR(200MHz,CDC1 3)δ12.24(s,1H),8.97(s,1H),8.85(s,1H),8.12(m,2H),7.70(m,2H),4.51(t,J=7.0Hz,2H),1.89(m,2H),1.56(m,2H),1.00(t,J=7.2Hz,3H)。
D) [(chloro-4-hydroxyl-benzo [g] isoquinoline 99.9-3-carbonyl)-amino]-acetate
Be similar to instance D-21e, make above-mentioned ester of 0.88g (2.7mmol) and glycine reactant.After the acidifying through filter collecting the gained throw out and dry to produce 0.30g (0.9mmol) product in high vacuum. 1H?NMR(200MHz,DMSO-d6)δ9.34(br?s,1H),9.00(s,1H),8.92(s,1H),8.34(m,2H),7.74(m,2H),3.94(d,J=5.4Hz,2H)。
Instance D-28
[(1-bromo-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
A) 1-bromo-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
With 2g (7.7mmol) 1,4-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester (from instance D-20b) is dissolved in the 100ml acetonitrile.Be added in the solution 15.4g (53.6mmol) bromine phosphorus oxide and at 80 ℃ of 64h that stir the mixture.100ml water is added into mixture and makes mixture leave thermal source.Mixture is divided between ETHYLE ACETATE and water to be dissolved.Separate two and also use the ethyl acetate extraction water layer mutually.Merge organic layer, with salt solution clean, via dried over mgso, filtration and evaporation.Through flash chromatography on silica gel method purifying resistates to produce 0.1g (0.3mmol) product. 1H?NMR(200MHz,CDCl 3)δ11.89(s,1H),8.41(m,1H),8.25(m,1H),7.84(m,2H),4.49(t,J=7.0Hz,2H),1.87(m,2H),1.47(m,2H),1.00(t,J=7.2Hz,3H)。
B) [(1-bromo-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
Be similar to instance D-21e, with the above-mentioned isoquinoline 99.9 ester of g (0.3mmol) and glycine reactant to produce the product of 0.08g (0.2mmol). 1H?NMR(200MHz,CD 3OD)δ8.94(br?s,1H),8.34(m,1H),8.24(m,1H),7.86(m,2H),4.18(d,J=6.2Hz,2H)。
Instance D-29
[(4-hydroxyl-6-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
According to being similar to the program of describing in detail among the instance D-37, prepare title compound by [(1-chloro-4-hydroxyl-6-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate (instance D-33).Final product uses in the methylene dichloride 0 to 15% methyl alcohol and 0.5% acetate gradient elution to want product to come purifying on silica gel through chromatography; MS (-): m/z 321.00 (M-1).
Instance D-30
[(4-hydroxyl-7-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
According to being similar to the program of describing in detail among the instance D-37, prepare title compound by [(1-chloro-4-hydroxyl-7-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate (instance D-34).Final product uses in the methylene dichloride 0 to 15% methyl alcohol and 0.5% acetate gradient elution to want product to come purifying on silica gel through chromatography; MS (-): m/z 321.02 (M-1).
Instance D-31
[(1-chloro-4-hydroxyl-6-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
A) (5-bromo-1,3-dioxy-1,3-dihydro-isoindole-2-yl)-methyl acetate
50.3g 4-bromine phthalic imidine, 92.0g salt of wormwood and 24.5ml methyl bromoacetate are added in the 888ml acetone.The gained mixture heating up to reflux temperature, is continued 24h, and then is cooled to room temperature.Filter this mixture through meticulous glass sintering filter and remove all solids material, and then under vacuum, concentrate this solution and wanted product so that the 66g solid that is white in color to be provided; 1H NMR (CDC1 3): δ=3.76 (s, 3H), 4.43 (s, 2H), 7.71-7.75 (m, lH), 7.85-7.90 (dd, 1H), 8.00 (m, 1H).
B) (1,3-dioxy-5-phenyl-1,3-dihydro-isoindole-2-yl)-methyl acetate
The above-mentioned bromine phthalic imidine of 6.0g product is dissolved in the 70ml glycol dimethyl ether.3.7g phenyl-boron dihydroxide, 13g cesium carbonate and 2g tetrakis triphenylphosphine palladium (0) are added so far in the solution.Under nitrogen atmosphere, stir this mixture 48h in 65 ℃.The gained mixture is injected 250ml semi-saturation sodium bicarbonate aqueous solution and then divides 3 extractions with 200ml ETHYLE ACETATE.Clean with 200ml water, saturated sodium bicarbonate and salt brine solution successively and merge organic part also then via dried over sodium sulfate.With solution concentration to resistates (11g), it uses in the hexane 0 to 25% ETHYLE ACETATE gradient elution to want product to come purifying on silica gel through chromatography.Obtain the 1.1g purified product; MS (+): m/z 296.02 (M+1)
C) 1,4-dihydroxyl-7-phenyl-isoquinoline-3-carboxylic acid butyl ester (A) and l, 4-dihydroxyl-6-phenyl-isoquinoline-3-carboxylic acid butyl ester (B)
The above-mentioned product of 1.4g is added in the butanol solution of 18.8ml 0.5N propyl carbinol sodium.With gained mixture heating up to 100 ℃, continue 2h, and then be cooled to room temperature.Mixture is injected 100ml 0.5N aqueous hydrochloric acid and divides 3 extractions with 100ml ETHYLE ACETATE.Filter and merge organic extract to remove any insoluble substance and then water and salt solution cleaning successively.Via this solution of dried over sodium sulfate and under vacuum, be concentrated into resistates (1.1g), it uses two primary products of 0 to 20% ETHYLE ACETATE gradient elution in the methylene dichloride to come purifying (R on silica gel through chromatography fIsomer A=0.64, R fB=0.48; 15% ETHYLE ACETATE: 85% methylene dichloride).
Isomer A:397mg; MS (+) m/z 388.11 (M+1)
Isomer B:195mg; MS (+) m/z 388.10 (M+1)
D) 1-chloro-4-hydroxyl-6-phenyl-isoquinoline-3-carboxylic acid butyl ester
Under the condition of in being similar to instance D-39d, describing in detail, use above-mentioned isomer B 1,4-dihydroxyl-6-phenyl-isoquinoline-3-carboxylic acid butyl ester prepares title compound; MS (+): m/z 356.06 (M+1)
E) [(1-chloro-4-hydroxyl-6-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
The following title compound that obtains: above-mentioned ester of 95mg and 300mg glycocoll are suspended in the methanol solution of 5.4ml 0.5N sodium methylate.This mixture heating up to reflux temperature, is continued 42h, and then is cooled to room temperature.Also clean with 30ml bicarbonate aqueous solution diluted mixture thing with 30ml ETHYLE ACETATE.Using the 6N aqueous hydrochloric acid is 3 with this acidified aqueous solution to pH value, and then divides 3 extractions with 35ml ETHYLE ACETATE.Merge organic extract and under vacuum, concentrate via dried over sodium sulfate and wanted product to produce the 73mg solid that is white in color; MS (-): m/z 354.99 (M-1).
Instance D-32
[(1-chloro-4-hydroxyl-7-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
According to being similar to the program of describing in detail among instance D-39d and the D-39e, by 1,4-dihydroxyl-7-phenyl-isoquinoline-3-carboxylic acid butyl ester (instance D-33c isomer A) prepares title compound.
1-chloro-4-hydroxyl-7-phenyl-isoquinoline-3-carboxylic acid butyl ester; MS (+): m/z 356.09 (M+1)
[(1-chloro-4-hydroxyl-7-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate; MS (-): m/z 355.01 (M-1)
Instance D-33
[(1-bromo-4-hydroxyl-6-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
With 161mg 1,4-dihydroxyl-6-phenyl-isoquinoline-3-carboxylic acid butyl ester (instance D-33c isomer B) is suspended in the 3ml anhydrous acetonitrile.Add 896mg bromine phosphorus oxide, and with this mixture heating up to reflux temperature, continue 5h.Mixture is cooled to room temperature, be evaporated to resistates and be suspended in 40ml ETHYLE ACETATE and the mixture of the 40ml sodium hydrogencarbonate semi-saturation aqueous solution in.Stir two-phase mixture 10min rapidly, and then divide 3 extractions with 40ml ETHYLE ACETATE.Under vacuum, concentrate and merge organic extract and on silica gel, use the main part of 0-5% ETHYLE ACETATE gradient elution in the methylene dichloride to come purifying through chromatography.Reclaim the 26mg material and directly be used for next reaction.
Resistates and 58mg glycocoll are suspended in the methanol solution of 1.4ml 0.5N sodium methylate.Mixture heating up to refluxing, is continued 18h, then be cooled to room temperature and be evaporated to about 0.5ml.Using 30ml water diluted mixture thing and using the 6N aqueous hydrochloric acid to be acidified to the pH value is 3.Collect the gained throw out and clean 2 times with cold water.Dried solid product under vacuum and obtain 16mg and want product; MS (-): m/z 398.90,400.92 (M-1, M+1; The Br isotropic substance).
Instance D-34
[(1-bromo-4-hydroxyl-7-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
Use is similar to the condition of describing in detail among the instance D-35, and by 1,4-dihydroxyl-7-phenyl-isoquinoline-3-carboxylic acid butyl ester (instance D-33c isomer A) prepares title compound.Final product uses in the methylene dichloride 0 to 10% methyl alcohol and 0.5% acetate gradient elution to want product to come purifying on silica gel through chromatography; MS (-): m/z 398.91,400.95 (M-1, M+1; The Br isotropic substance).
Instance D-35
[(4-hydroxyl-5-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
To be suspended in the solution of 12ml MeOH and 4ml water from 200mg [(1-chloro-4-hydroxyl-5-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate of instance D-39e.Add 45mg yellow soda ash and 100mg 10 weight % palladium/activated carbon and under the nitrogen atmosphere that provides by the ball that is filled with hydrogen, stir this mixture 18h.Also then filter with methyl alcohol and sodium bicarbonate aqueous solution dilution gained mixture through Celite pad.This solution of concentrating under reduced pressure then is diluted to 30ml with the semi-saturation bicarbonate solution to about 6ml, and then to use concentrated hydrochloric acid aqueous solution to be acidified to the pH value be 3.Divide extraction water solution 3 times with 30ml ETHYLE ACETATE.Merge organic extract and concentrating under reduced pressure via dried over sodium sulfate and wanted product so that the 107mg solid that is white in color to be provided; MS (+): m/z 323.08 (M+1).
Instance D-36
[(4-hydroxyl-8-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
Use is similar to the condition of describing in detail among the instance D-37, prepares title compound by [(1-chloro-4-hydroxyl-8-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate (instance D-40); MS (+): m/z 323.06 (M+1).
Instance D-37
[(1-chloro-4-hydroxyl-5-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
A) xenyl-2, the 3-dioctyl phthalate
15g of2-methyl-3-xenyl methyl alcohol and 75mg cetrimonium bromide are added in the 150ml water, and in ice bath, the gained mixture are cooled to 0 ℃.48g potassium permanganate is added in the cold mixt and at 0 ℃ of following reaction stirred 10min, at room temperature stirs 16h, then stir 48h down at 70 ℃.Filter the settled solution that contains black solid through Celite pad, and clean with the 100ml methylene dichloride.Then using the 6N aqueous hydrochloric acid is 3 with this acidified aqueous solution to pH value, and then divides 4 extractions with 150ml ETHYLE ACETATE.Merge organic part via anhydrous sodium sulfate drying, and be concentrated into the 12.9g product; 1HNMR (d6-DMSO): δ=7.28-7.46 (m, 5H), 7.51-7.61 (m, 2H), 7.84-7.89 (dd, 1H), 13.0 (s, 2H).
B) (1,3-dioxy-4-phenyl-1,3-dihydro-isoindole-2-yl)-methyl acetate
With mortar that the above-mentioned diprotic acid of 10.5g and 3.25g glycocoll is mixed and grind and then in the oil bath that remains between 210 to 230 ℃, heat 15min.Cool off this mixture and the gained solid directly is used for next reaction.
The thick phthalic imidine product that 7.4g salt of wormwood and 5.7ml methyl-sulfate are added into from above-mentioned reaction is dissolved in the solution of 125ml acetone.This mixture heating up to reflux temperature, is continued 24h, and then is cooled to room temperature.Clean this mixture and with 500ml ethyl acetate extraction 3 times with 500ml water.With organic part of salt solution cleaning merging and via dried over sodium sulfate.Concentrate this solution and with the gained solid from ETHYLE ACETATE crystallization to obtain the 5.0g light yellow solid; 1HNMR (CDC1 3): δ=3.74 (s, 3H), 4.40 (s, 2H), 7.91-7.43 (m, 8H).
C) 1,4-dihydroxyl-8-phenyl-isoquinoline-3-carboxylic acid butyl ester (A) and l, 4-dihydroxyl-5-phenyl-isoquinoline-3-carboxylic acid butyl ester (B)
The above-mentioned product of 5.07g is added in the butanol solution of 68.8ml 0.5N propyl carbinol sodium.With gained mixture heating up to 95 ℃, continue 4h, and then be cooled to room temperature.Add 2.1ml acetate and this mixture of concentrating under reduced pressure to about 15ml volume.With semi-saturation sodium hydrogen carbonate solution dilution crude product and with ethyl acetate extraction 3 times.Water, then clean with salt solution and merge organic part and via dried over sodium sulfate.Concentrate this solution and on silica gel, use two the main parts of 0 to 25% ETHYLE ACETATE gradient elution in the methylene dichloride to come purifying resistates (5.3g) (R through chromatography fIsomer A=0.68, R fB=0.52,15% ETHYLE ACETATE: 85% methylene dichloride):
Isomer A, 2.19g; MS (+) m/z 338.15 (M+1)
Isomer B, 1.22g; MS (+) m/z 388.04 (M+1)
D) 1-chloro-4-hydroxyl-5-phenyl-isoquinoline-3-carboxylic acid butyl ester
500mg is suspended in the 5ml phosphorus oxychloride from the isomer B of above-mentioned reaction and is heated to 100 ℃, continue 1h.Reaction mixture is evaporated to resistates and then with 30ml water and the dilution of 30ml ETHYLE ACETATE, the while stirs rapidly.The pH of monitoring water also is adjusted to the pH value and is about 7 through adding sodium hydrogencarbonate.Stir two-phase mixture 30min, and then with 30ml ethyl acetate extraction 3 times.Cleaning merging with saturated sodium bicarbonate solution and salt solution also follows via dried over sodium sulfate for organic part.This solution of concentrating under reduced pressure, and on silica gel, use the main part of one of 5 to 20% ETHYLE ACETATE gradient elution in the methylene dichloride to come purifying resistates (494mg) through chromatography.Obtain the 442mg purified product; MS: (+) m/z 355.99 (M+1).
E) [(1-chloro-4-hydroxyl-5-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
Above-mentioned ester of 435mg and 1.0g glycocoll are suspended in the methanol solution of 24.4ml 0.5N sodium methylate.Mixture heating up to refluxing, is continued 18h, then be cooled to room temperature and be evaporated to about 5ml.Using 50ml water diluted mixture thing and using the 1N aqueous hydrochloric acid to be acidified to the pH value is 3.Collect the gained throw out and clean 2 times with cold water.Dried solid product under vacuum and obtain the 414mg product; MS (+) m/z 356.99 (M+1).
Instance D-38
[(1-chloro-4-hydroxyl-8-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
Use is similar to the condition of describing in detail among instance D-39d and the D-39e, and by 1,4-dihydroxyl-8-phenyl-isoquinoline-3-carboxylic acid butyl ester (instance D-39c isomer A) prepares title compound.
1-chloro-4-hydroxyl-8-phenyl-isoquinoline-3-carboxylic acid butyl ester; MS (+): m/z 356.05 (M+1)
[(1-chloro-4-hydroxyl-8-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate; MS (+): m/z 356.99 (M+1)
Instance D-39
[(1-bromo-4-hydroxyl-5-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
A) 1-bromo-4-hydroxyl-5-phenyl-isoquinoline-3-carboxylic acid butyl ester
Will be from the 411mg 1 of instance D-39c isomer B, 4-dihydroxyl-5-phenyl-isoquinoline-3-carboxylic acid butyl ester is suspended in the 15ml anhydrous acetonitrile.Add 2.0g bromine phosphorus oxide and reaction mixture is heated to backflow, continue 3.5h.Reaction mixture also is injected in the saturated sodium bicarbonate aqueous solution of 0 ℃ of 75ml.Stir this mixture 5min, and then divide 3 extractions with 75ml ETHYLE ACETATE.Clean organic part of merging with salt solution, via dried over sodium sulfate and concentrating under reduced pressure.On silica gel, use 0 to 25% ETHYLE ACETATE gradient elution in the hexane to come purifying resistates (434mg) through chromatography as one main part product.Obtain 480mg and want product; MS (+): m/z 422.02 (M+23).
B) [(1-bromo-4-hydroxyl-5-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
The following title compound that obtains: above-mentioned ester of 200mg and 412mg glycocoll are suspended in the methanol solution of 10ml 0.5N sodium methylate.Mixture heating up to refluxing, is continued 24h, then be cooled to room temperature and be evaporated to about 3ml.Using 50ml water diluted mixture thing and using the 1N aqueous hydrochloric acid to be acidified to the pH value is 3.Collect the gained throw out and clean 2 times with cold water.Dried solid product under vacuum and obtain the 188mg product; MS (-): m/z 398.96,400.95 (M-1, M+1; The Br isotropic substance).
Instance D-40
[(1-bromo-4-hydroxyl-8-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
Use is similar to the condition of describing in detail among the instance D-41, and by 1,4-dihydroxyl-8-phenyl-isoquinoline-3-carboxylic acid butyl ester (instance D-39c isomer A) prepares title compound.
1-bromo-4-hydroxyl-8-phenyl-isoquinoline-3-carboxylic acid butyl ester; MS (+): m/z 400.00,402.03 (M+1, M+3; The Br isotropic substance).
[(1-bromo-4-hydroxyl-8-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate; MS (-): m/z 398.95,400.98 (M-1, M+1; The Br isotropic substance)
Instance D-41
[(1-ethyl sulfenyl-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
A) 1-ethyl sulfenyl-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
With 52mg 1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (instance D-20c) be dissolved in the 2ml sulfur alcohol and in ST in 70 ℃ the heating 24h, and 100 ℃ the heating 48h.Under vacuum, concentrate gained solution and on silica gel, use 0 to 20% ETHYLE ACETATE gradient elution product in the hexane to come purifying resistates (54mg) through chromatography.Obtain the 25mg product; MS (+): m/z 306.06 (M+1)
B) [(1-ethyl sulfenyl-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
Under the condition of in being similar to instance D-39e, describing in detail, use above-mentioned ester to obtain title compound; MS (-) m/z 304.98 (M-1).
Instance D-42
{ [4-hydroxyl-1-(4-methoxyl group-phenyl sulfenyl)-isoquinoline 99.9-3-carbonyl]-amino }-acetate
1ml 4-anisole mercaptan is added into 100mg [(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate (USP 6; 093; 730, be disclosed as N-((1-chloro-4-hydroxyl isoquinoline 99.9-3-yl) carbonyl) glycocoll) be dissolved in 1ml N, in the solution in the dinethylformamide.In ST, heat 72h with under in 120 to 130 ℃ of this solution.Then solution is concentrated under vacuum.On silica gel, use 0 to 15% methyl alcohol and 0.5% acetate gradient elution product in the methylene dichloride to come purifying gained resistates (76mg) through chromatography.Obtain the 6mg product; MS (+) m/z 385.05 (M+1)
Instance D-43
[(1-chloro-4-hydroxyl-7-iodo-isoquinoline 99.9-3-carbonyl)-amino]-acetate
A) (5-iodo-1,3-dioxy-1,3-dihydro-isoindole-2-yl)-acetate
Make 10g 4-iodo-phthalic acid and 2.63g glycocoll closely mixed and, continue 10min this mixture heating up to 200 ℃.After the cooling,, concentrating the pale brown look solid of back generation 6.40g with ethyl acetate extraction solid reaction mixture: MS-(-)-ion, proton N MR (200MHz, methyl alcohol-d-4): δ 8.26-8.18 (m, 2H), 7.68-7.61 (m, 1H), 4.39 (s, 1H).
B) (5-iodo-1,3-dioxy-1,3-dihydro-isoindole-2-yl)-methyl acetate
With 2.7g methyl-sulfate in the 25ml backflow acetone and 3.0g salt of wormwood esterification 6.4g instance D-55a) formic acid product 3h.With ETHYLE ACETATE diluted reaction mixture, filtration and concentrated.Resistates is dissolved in the fresh ethyl and cleans (water, salt solution) organic layer and via dried over sodium sulfate.The warp of concentrate drying filters ethyl acetate solution and produces the little yellow solid of 5.8g.Proton N MR (200MHz, chloroform-d): δ 8.24-8.20 (m, 1H), 8.14-8.06 (m, 1H), 7.62-7.56 (d, 1H), 4.40 (s, 2H), 3.75 (s, 3H).
C) 4-hydroxyl-7-iodo-1-oxygen-1,2-dihydro-isoquinoline-3-butyl formate and 4-hydroxyl ~ 6-iodo-1-oxygen-1,2-dihydro-isoquinoline-3-carboxylic acid butyl ester
Under nitrogen atmosphere in 65 ℃ of sodium dissolving metals with the fresh incision of 0.40g in the 22ml propyl carbinol.3.0g (5-iodo-1,3-dioxy-1,3-dihydro-isoindole-2-the yl)-mixture of methyl acetate in the 22ml propyl carbinol is added in the sodium butylate solution and with reaction mixture and is heated to 80 ℃, continue 2h.Produce solid sediment with 100ml1M hcl acidifying refrigerative reaction mixture.(elutriant: 19: 1 methylene dichloride: ETHYLE ACETATE) separation produces 0.219g 4-hydroxyl-7-iodo-1-oxygen-1 through solid collected by filtration and through silica gel chromatography; 2-dihydro-isoquinoline-3-carboxylic acid butyl ester: MS-(-)-ion; M-1=386.0amu and 0.150g 4-hydroxyl-6-iodo-1-oxygen-1; 2-dihydro-isoquinoline-3-carboxylic acid butyl ester: MS-(-)-ion, M-1=386.0amu.
D) 1-chloro-4-hydroxyl-7-iodo-isoquinoline-3-carboxylic acid butyl ester
At room temperature with 0.215g 4-hydroxyl-7-iodo-1-oxygen-1,2-dihydro-isoquinoline-3-carboxylic acid butyl ester is added into 5ml POCl 3In.With reflux 3h and under vacuum, remove POCl of mixture 3Resistates is dissolved in the ETHYLE ACETATE and cleans this solution, drying (MgSO with saturated sodium bicarbonate aqueous solution 4), filter and concentrate with produce 0.205g white solid: proton N MR (200MHz, the δ 11.91 of chloroform-d) (s, 1H), 8.67 (m, 1H), 8.10 (m; 2H), 4.49 (t, J=7Hz, 2H), 1.95-1.75 (m, 2H); 1.60-1.39 (m, 2H), 1.00 (t, J=7Hz, 3H).
E) [(1-chloro-4-hydroxyl-7-iodo-isoquinoline 99.9-3-carbonyl)-amino]-acetate
Be added in the mixture of 0.263g glycocoll in 4.7ml 0.5M sodium methylate 0.095g 1-chloro-4-hydroxyl-7-iodo-isoquinoline-3-carboxylic acid butyl ester and this reaction mixture 18h that refluxes.Concentrate this mixture, resistates is dissolved in the water and with this solution of 1M hcl acidifying.Clean organic layer, drying (MgSO with ethyl acetate extraction throw out and water 4), filter and concentrate to produce the 0.079g light yellow product: MS-(-)-ion, M-1=406.9amu,
Instance D-44
[(1-chloro-4-hydroxyl-6-iodo-isoquinoline 99.9-3-carbonyl)-amino]-acetate
A) 1-chloro-4-hydroxyl-6-iodo-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance D-43d), make 0.150g 4-hydroxyl-6-iodo-1-oxygen-1,2-dihydro-isoquinoline-3-carboxylic acid butyl ester and 5mlPOC1 3Reaction is to provide 0.057g shallow white solid: proton N MR (200MHz, chloroform-d): δ 11.9 (s, 1H), 8.89 (m, 1H), 8.1 (m, 1H); 7.97 (m, 1H), 4.5 (t, J=7Hz, 2H), 2.0-1.8 (m; 2H), 1.65-1.4 (m, 2H), 1.00 (t, J=7Hz, 3H).
B) [(1-chloro-4-hydroxyl-6-iodo-isoquinoline 99.9-3-carbonyl)-amino]-acetate
Be similar to instance D-55e) condition under; Make 0.053g come from instance D-44a) butyl ester and the mixture reaction of 0.147g glycocoll in the methanol solution of 2.6ml 0.5M sodium methylate produce 0.047g and be creamy white solid product: MS-(-)-ion, M-1=406.9amu.
Instance D-45
[(4-hydroxyl-7-iodo-isoquinoline 99.9-3-carbonyl)-amino]-acetate
A) 4-hydroxyl-7-iodo-isoquinoline-3-carboxylic acid butyl ester
With 0.100g from instance D-43d) product be dissolved in 1.5ml and contain in the Glacial acetic acid min. 99.5 of 0.015g red phosphorus and 56 microlitre hydroiodic acid HIs (d=1.701g/ml).Reaction mixture refluxed 1h filters with the ETHYLE ACETATE dilution and through plug of celite.Clean filtrate, drying (MgSO with saturated aqueous sodium thiosulfate and saturated sodium bicarbonate aqueous solution 4), filter and concentrate to produce crude product.Crude product is used silica gel chromatography (elutriant: 99: 1CH 2Cl 2-ETHYLE ACETATE) produce the 0.073g white solid.Proton N MR (200MHz, chloroform-d): δ 11.9 (s, 1H), 8.70 (s, 1H), 8.40-8.30 (m, 1H); 8.12-8.05 (m, 1H), 8.05-7.96 (m, 1H), 4.48 (t, J=7Hz, 2H); 1.95-1.80 (m, 2H), 1.60-1.40 (m, 2H), 0.99 (t, J=7Hz, 3H).
B) [(4-hydroxyl-7-iodo-isoquinoline 99.9-3-carbonyl)-amino]-acetate
Be similar to instance D-55e), make from instance D-45a) butyl ester and the mixture reaction of 0.142g glycocoll in 2.5ml 0.5M methanol solution of sodium methylate obtain 0.042g.MS-(-)-ion, M-1=373.0amu.
Instance D-46
[(1-bromo-4-hydroxyl-7-methyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
A) 4-hydroxyl-7-methyl isophthalic acid-oxygen-1,2-dihydro-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance D-43a)-D-43c) reaction sequence after, 5.0g 4-methyl-phthalic acid produces 0.213g 4-hydroxyl-7-methyl isophthalic acid-oxygen-1,2-dihydro-isoquinoline-3-carboxylic acid butyl ester: MS-(-)-ion, M-1=274.1amu.
B) 1-bromo-4-hydroxyl-7-methyl-isoquinoline-3-carboxylic acid butyl ester
Will be from instance D-46a) the 0.210g ester products be added in the 3.5ml acetonitrile.Add 1.52g bromine phosphorus oxide and with this mixture backflow 6h, cool off and be dissolved in the ETHYLE ACETATE.Use saturated NaHCO 3The aqueous solution cleans ethyl acetate solution, drying (MgSO 4), filter and concentrate to produce the 0.266g crude product.To crude product use silica gel chromatography (elutriant: methylene dichloride) with produce 0.094g white solid: proton N MR (200MHz, chloroform-d): δ 11.85 (s, 1H), 8.30-8.20 (d, 1H), 8.00 (br s; 1H), and 7.70-7.60 (m, 1H), 4.47 (t, J=7Hz; 2H), 2.62 (s, 3H), 1.95-1.75 (m, 2H); 1.60-1.35 (m, 2H), 1.00 (t, J=7Hz, 3H).
C) [(1-bromo-4-hydroxyl-7-methyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
Be similar to instance D-55e), make 0.094g from instance D-46b) butyl ester and the mixture reaction of 0.312g glycocoll in the 5.5ml0.5M methanol solution of sodium methylate produce 0.083g creamy white solid: MS-(-)-ion, M-1=339.0amu.
Instance D-47
[(1-bromo-7-butoxy-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
A) 1-bromo-7-butoxy-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance D-46b), make 0.150g 7-butoxy-4-hydroxyl-1-oxygen-1, the reaction of 2-dihydro-isoquinoline-3-carboxylic acid butyl ester and bromine phosphorus oxide with produce 0.105g creamy white solid: proton N MR (200MHz, chloroform-d): δ 11.82 (s, 1H), 8.68 (s, 1H); 8.26 (d, 1H), 7.35 (dd, 1H), 7.19 (d, 1H); 4.49 (t, J=7Hz, 2H), 4.12 (t, J=7Hz, 2H); 1.95-1.75 (m, 4H), 1.70-1.40 (m, 4H), 1.05-0.95 (m, 6H).
B) [(1-bromo-7-butoxy-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
Be similar to instance D-11e), make 0.100g from instance D-47a) butyl ester and the mixture reaction of glycocoll in methanol solution of sodium methylate to produce the 0.094g white solid: MS-(-)-ion, M-1=397.0amu.
Instance D-48
[(1-bromo-6-butoxy-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
A) 1-bromo-6-butoxy-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance D-46b), make the reaction of 0.175g 6-butoxy-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester and bromine phosphorus oxide with produce 0.073g white solid: proton N MR (200MHz, chloroform-d): δ 11.84 (s, 1H), 8.13 (d, 1H); 7.60 (m, 1H), 7.42-7.35 (m, 1H), 4.48 (t, J=7Hz; 2H), 4.15 (t, J=7Hz, 2H), 1.95-1.75 (m; 4H), and 1.65-1.40 (m, 4H), 1.05-0.95 (m, 6H).
B) [(1-bromo-6-butoxy-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
Be similar to instance D-43e), make 0.068g from instance D-48a) butyl ester and the mixture reaction of glycocoll in methanol solution of sodium methylate to produce 0.063g creamy white solid: MS-(-)-ion, M-1=397.0amu.
Instance D-49
[(6-benzyloxy-1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-methyl-amino]-acetate
With 0.33g 6-benzyloxy-1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid, 0.5ml triethylamine, 0.400g HATU and 0.165g N-methyl-amino-ethyl acetate hydrochloride in the 15ml methylene dichloride mixed and at room temperature stirred reaction mixture 18h behind silica gel chromatography, to produce 0.232g creamy white solid, MS-(+)-ion: 429.0amu.This intermediate product of 0.208g is dissolved in the 10ml NaOH methanol solution (1.5M) and at room temperature stirs this mixture 3h.Remove solvent with rotary evaporator, resistates is dissolved in the water and with 50ml ethyl acetate extraction water layer.Use the HCl aqueous solution with the water layer acidifying as pH=1 to produce solid sediment.Collect solid through suction filtration, water cleans and is dry to produce the 0.180g white solid in vacuum drying oven (80 ℃): MS-(+)-ion: 401.0amu.
Instance D-50
[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-methyl-amino]-acetate
Be similar to instance D-49, prepare by 1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid: MS-(+)-ion: 294.9amu.
Instance D-51
[(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-methyl-amino]-acetate
Be similar to instance D-49, prepare by 1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline-3-carboxylic acid: MS-(+)-ion: 353.0amu.
Instance D-52
[(1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline 99.9-3-carbonyl)-methyl-amino]-acetate
Be similar to instance D-49, prepare by 1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline-3-carboxylic acid: MS-(+)-ion: 353.0amu.
Instance D-53
[ethyloic-(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
Be similar to instance D-49, prepare by 1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid and (oxyethyl group carbonyl methyl-amino)-ETHYLE ACETATE: MS-(+)-ion: 339.0amu.
Instance D-54
[ethyloic-(1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline 99.9-3-carbonyl)-amino]-acetate
Be similar to instance D-49, prepare by 1-chloro-4-hydroxyl-6-isopropoxy-isoquinoline-3-carboxylic acid and (oxyethyl group carbonyl methyl-amino)-ETHYLE ACETATE: MS-(+)-ion: 397.0amu.
Instance D-55
{ [4-hydroxyl-1-(naphthalene-2-base oxygen base)-isoquinoline 99.9-3-carbonyl]-amino }-acetate
A) 4-hydroxyl-1-(naphthalene-2-base oxygen base)-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance D-20d), synthetic by 1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester and naphthalene-2-alcohol; MS-(+)-ion: M+1=388.1.
B) { [4-hydroxyl-1-(naphthalene-2-base oxygen base)-isoquinoline 99.9-3-carbonyl]-amino }-acetate
Be similar to instance D-1g), (naphthalene-2-base oxygen base)-the isoquinoline-3-carboxylic acid butyl ester is synthetic by 4-hydroxyl-1-; MS-(+)-ion: M+1=389.1.
Instance D-56
{ [4-hydroxyl-1-(pyridin-3-yl oxygen base)-isoquinoline 99.9-3-carbonyl]-amino }-acetate
A) 4-hydroxyl-1-(pyridin-3-yl oxygen base)-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance D-20d), synthetic by 1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester and pyridine-3-alcohol; MS-(+)-ion: M+1=339.1.
B) { [4-hydroxyl-1-(pyridin-3-yl oxygen base)-isoquinoline 99.9-3-carbonyl]-amino }-acetate
Be similar to instance D-1g), synthetic by 4-hydroxyl-1-(pyridin-3-yl oxygen base)-isoquinoline-3-carboxylic acid butyl ester; MS-(+)-ion: M+1=340.1.
Instance D-57
{ [4-hydroxyl-1-(4-methoxyl group-phenoxy)-isoquinoline 99.9-3-carbonyl]-amino }-acetate
A) 4-hydroxyl-1-(4-methoxyl group-phenoxy)-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance D-20d), synthetic by 1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester and 4-methoxyl group-phenol; MS-(+)-ion: M+1=368.1.
B) { [4-hydroxyl-1-(4-methoxyl group-phenoxy)-isoquinoline 99.9-3-carbonyl]-amino }-acetate
Be similar to instance D-1g), synthetic by 4-hydroxyl-1-(4-methoxyl group-phenoxy)-isoquinoline-3-carboxylic acid butyl ester; MS-(+)-ion: M+1=369.1.
Instance D-58
{ [4-hydroxyl-1-(3-methoxyl group-phenoxy)-isoquinoline 99.9-3-carbonyl]-amino }-acetate
A) 4-hydroxyl-1-(3-methoxyl group-phenoxy)-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance D-20d), synthetic by 1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester and 3-methoxyphenol; MS-(+)-ion: M+1=368.1.
B) { [4-hydroxyl-1-(3-methoxyl group-phenoxy)-isoquinoline 99.9-3-carbonyl]-amino }-acetate
Be similar to instance D-1g), synthetic by 4-hydroxyl-1-(3-methoxyl group-phenoxy)-isoquinoline-3-carboxylic acid butyl ester; MS-(-)-ion: M-1=367.0.
Instance D-59
{ [1-(3-fluoro-phenoxy)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate
A) 1-(3-fluoro-phenoxy)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance D-20d), synthetic by 1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester and 3-fluorophenol; MS-(+)-ion: M+1=356.1.
B) { [1-(3-fluoro-phenoxy)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate
Be similar to instance D-1g), synthetic by 1-(3-fluoro-phenoxy)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester; MS-(+)-ion: M+1=357.09.
Instance D-60
{ [1-(4-fluoro-phenoxy)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate
A) 1-(4-fluoro-phenoxy)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance D-20d), synthetic by 1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester and 4-fluorophenol; MS-(+)-ion: M+1=356.1.
B) { [1-(4-fluoro-phenoxy)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate
Be similar to instance D-1g), synthetic by 1-(4-fluoro-phenoxy)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester; MS-(+)-ion: M+1=357.0.
Instance D-61
{ [1-(2-fluoro-phenoxy)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate
A) 1-(2-fluoro-phenoxy)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance D-20d), synthetic by 1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester and 2-fluorophenol; MS-(+)-ion: M+1=356.1.
B) { [1-(2-fluoro-phenoxy)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate
Be similar to instance D-1g), synthetic by 1-(2-fluoro-phenoxy)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester; MS-(+)-ion: M+1=357.11.
Instance D-62
{ [4-hydroxyl-1-(2-methoxyl group-phenoxy)-isoquinoline 99.9-3-carbonyl]-amino }-acetate
A) 4-hydroxyl-1-(2-methoxyl group-phenoxy)-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance D-20d), synthetic by 1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester and 2-methoxyphenol; MS-(+)-ion: M+1=368.13.
B) { [4-hydroxyl-1-(2-methoxyl group-phenoxy)-isoquinoline 99.9-3-carbonyl]-amino }-acetate
Be similar to instance D-1g), synthetic by 4-hydroxyl-1-(2-methoxyl group-phenoxy)-isoquinoline-3-carboxylic acid butyl ester; MS-(+)-ion: M+1=369.09.
Instance D-63
{ [1-(4-acetylaminohydroxyphenylarsonic acid phenoxy)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate
A) 4-acetoxyl group-1-(4-acetylaminohydroxyphenylarsonic acid phenoxy)-isoquinoline-3-carboxylic acid butyl ester
At ambient temperature with 4-hydroxyl-1-phenoxy-isoquinoline-3-carboxylic acid butyl ester (261mg, 0.77mmol; See instance D-20d) be dissolved in dense H 2SO 4(4ml).Solution is cooled to 0 ℃ also under agitation slowly adds KNO 3(79mg, 0.77mmol).Mixture is stirred 2h down at 0 ℃, under agitation be injected into then in the frozen water (100ml).(3 * 30ml) extract this mixture with EtOAc.Use NaHCO 3The aqueous solution and salt solution clean and merge organic phase, dry and concentrated in a vacuum.Resistates is dissolved in the mixture of EtOAc (20ml) and MeOH (10ml).Add sodium acetate (70mg, 0.85mmol) and Pd/C (75mg, 10 weight %Pd) and at H 2Stir this mixture 24h in envrionment temperature under the-atmosphere (1atm).Then filter this mixture through Celite pad.(3 * 4ml) clean zeyssatite and filter cake and concentrate the merging organic phase in a vacuum with hot MeOH.150mg gained resistates (is amounted to: 380mg) be dissolved among the EtOAc (8ml).(325 μ l 2.3mmol) and with solution are cooled to 0 ℃ to add triethylamine.Then under vigorous stirring, slowly add diacetyl oxide (110 μ l, 1.15mmol).Make this mixture temperature to envrionment temperature also then stir 20h whole night at ambient temperature again.Add EtOAc (50ml) subsequently.Use NaHCO 3The aqueous solution and salt solution washed mixture, dry and concentrated in a vacuum.On silica gel, use CH through flash chromatography 2Cl 2: MeOH=100: came the purifying resistates to produce 150mg 4-acetoxyl group-1-(4-acetylaminohydroxyphenylarsonic acid phenoxy)-isoquinoline-3-carboxylic acid butyl ester as elutriant in 1 to 100: 3; MS-(+)-ion: M+1=437.11.
B) { [1-(4-acetylaminohydroxyphenylarsonic acid phenoxy)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate
Under agitation with 4-acetoxyl group-1-(4-acetylaminohydroxyphenylarsonic acid phenoxy)-isoquinoline-3-carboxylic acid butyl ester (150mg; 0.34mmol), (290mg is 3.4mmol) with the mixture backflow complete cycle of methyl alcohol (3.9mmol) solution of 7.8ml 0.5N sodium methylate for glycocoll.Then evaporating solvent and resistates is dissolved in the 25ml water in a vacuum.PH value with this solution is adjusted into about 2 also with the ETHYLE ACETATE (slurries of 3 * 30ml) extraction gained subsequently.Via MgSO 4Dry combining extraction liquid and evaporation in a vacuum.Make resistates from methyl alcohol/CH 2Cl 2Middle recrystallize produces the 86mg title compound; MS-(+)-ion: M+1=396.15.
Instance D-64
{ [4-hydroxyl-1-(4-methanesulfonamido-phenoxy)-isoquinoline 99.9-3-carbonyl]-amino }-acetate
At ambient temperature with 4-hydroxyl-1-phenoxy-isoquinoline-3-carboxylic acid butyl ester (261mg, 0.77mmol; See instance D-20d) be dissolved in dense H 2SO 4(4ml).Solution is cooled to 0 ℃ also under agitation slowly adds KNO 3(79mg, 0.77mmol).Mixture is stirred 2h down at 0 ℃, under agitation be injected into then in the frozen water (100ml).(3 * 30ml) extract this mixture with EtOAc.Use NaHCO 3The aqueous solution and salt solution clean and merge organic phase, dry and concentrated in a vacuum.Resistates is dissolved in the mixture of EtOAc (20ml) and MeOH (10ml).Add sodium acetate (70mg, 0.85mmol) and Pd/C (75mg, 10 weight %Pd) and at H 2Stir this mixture 24h in envrionment temperature under the-atmosphere (1atm).Then filter this mixture through Celite pad.(3 * 4ml) clean zeyssatite and filter cake and concentrate the merging organic phase in a vacuum with hot MeOH.150mg gained resistates (is amounted to: 380mg) be dissolved in CH 2Cl 2(8ml).Add triethylamine (165 μ l) and solution is cooled to-20 ℃.Then under vigorous stirring, slowly add MeSO 2Cl (36 μ l).Make this mixture temperature to envrionment temperature also then stir 20h whole night at ambient temperature again.Add EtOAc (50ml) subsequently.Use NaHCO 3The aqueous solution and salt solution washed mixture, dry and concentrated in a vacuum.On silica gel, use CH through flash column chromatography 2Cl 2: MeOH=100: 0-100: 3 come the purifying resistates as elutriant.(290mg 3.4mmol) is added in the purified product (168mg) and with this mixture with methyl alcohol (3.9mmol) solution of 7.8ml 0.5N sodium methylate and under agitation refluxes a weekend with glycocoll.Then evaporating solvent and resistates is dissolved in the 30ml water in a vacuum.PH value with this solution is adjusted into about 2 also with the ETHYLE ACETATE (mixture of 3 * 30ml) extraction gained subsequently.Via MgSO 4Dry combining extraction liquid and evaporation in a vacuum.Make resistates from methyl alcohol/CH 2Cl 2Middle recrystallize produces the 89mg title compound; MS-(+)-ion: M+1=432.12.
Instance D-65
[(4-hydroxyl-1-phenyl amino-isoquinoline 99.9-3-carbonyl)-amino]-acetate
A) 4-hydroxyl-1-phenyl amino-isoquinoline-3-carboxylic acid butyl ester
150 ℃ of mixture 20min that stir 1-bromo-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (810mg, 2.5mmol, instance D-28a) and aniline (3ml) in the pressure tube in microwave oven.Merge two kinds of reaction mixtures, add EtOAc (100ml) and use H 2(5 * 30ml pH=1-2) cleans this mixture to O.Dry organic phase also concentrates in a vacuum.On silica gel, make hexane/EtOAc come the purifying resistates to produce 770mg 4-hydroxyl-1-phenyl amino-isoquinoline-3-carboxylic acid butyl ester through flash chromatography as elutriant; MS-(+)-ion: M+1=337.21.
B) [(4-hydroxyl-1-phenyl amino-isoquinoline 99.9-3-carbonyl)-amino]-acetate
Be similar to instance D-1g), synthetic by hydroxyl-1-phenyl amino-isoquinoline-3-carboxylic acid butyl ester; MS-(+)-ion: M+1=338.14.
Instance D-66
{ [4-hydroxyl-6-(pyridin-3-yl oxygen base)-isoquinoline 99.9-3-carbonyl]-amino }-acetate
A) 4-(pyridin-3-yl oxygen base)-phthalonitrile
Stir at ambient temperature 4-nitro-phthalonitrile (3.46g, 20mmol), pyridine-3-alcohol (1.90g, 20mmol), K 2CO 3(8.29g, 60mmol) and the mixture of DMF (50ml) whole night.Then with reaction mixture and another batch merging of on identical scale, carrying out same reaction.Remove solid constituent and concentrating filtrate in a vacuum through filtration subsequently.Water (15ml) is added in the resistates and with this mixture of EtOAc extraction.Then clean organic phase, dry and evaporation in a vacuum with salt solution.Make resistates from EtOAc/MeOH recrystallize to produce the 8.3g title compound; 1H NMR (CDCl 3): δ=8.56-8.59 (m, 1H), 8.45-8.47 (m, 1H), 7.76 (d, 1H), 7.42-7.44 (m, 2H), 7.22-7.32 (m, 2H).
B) 4-(pyridin-3-yl oxygen base)-phthalic acid
Be similar to instance D-1a) synthetic by 4-(pyridin-3-yl oxygen base)-phthalonitrile; MS-(+)-ion: M+1=260.2.
C) [1,3-dioxy-5-(pyridin-3-yl oxygen base)-1,3-dihydro-isoindole-2-yl]-acetate
Be similar to instance D-1b) synthetic by 4-(pyridin-3-yl oxygen base)-phthalic acid; MS-(+)-ion: M+1=299.25.
D) [1,3-dioxy-5-(pyridin-3-yl oxygen base)-1,3-dihydro-isoindole-2-yl)-methyl acetate
Be similar to instance D-1c) synthetic by [1,3-dioxy-5-(pyridin-3-yl oxygen base)-1,3-dihydro-isoindole-2-yl]-acetate; MS-(+)-ion: M+1=313.21.
E) 1,4-dihydroxyl-6-(pyridin-3-yl oxygen base)-isoquinoline-3-carboxylic acid butyl ester and 1,4-dihydroxyl-7-(pyridin-3-yl oxygen base)-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance D-1d) synthetic by [1,3-dioxy-5-(pyridin-3-yl oxygen base)-1,3-dihydro-isoindole-2-yl]-methyl acetate.But, after adding 2N HCl (the pH value is adjusted into 8-9), extract this mixture 3 times with EtOAc.The dry organic phase and concentrated in a vacuum that merges.Handle resistates and in refrigerator, store whole night with MeOH.Filter formed throw out, with small amount of cold MeOH clean and dried in vacuum with the be white in color regional isomerism mixture of solid title compound of generation.1,4-dihydroxyl-6-(pyridin-3-yl oxygen base)-isoquinoline-3-carboxylic acid butyl ester and 1,4-dihydroxyl-7-(pyridin-3-yl oxygen base)-isoquinoline-3-carboxylic acid butyl ester does not separate; MS-(+)-ion: M+1=355.09.
F) 1-chloro-4-hydroxyl-6-(pyridin-3-yl oxygen base)-isoquinoline-3-carboxylic acid butyl ester and 1-chloro-4-hydroxyl-7-(pyridin-3-yl oxygen base)-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance D-43d), by [1,4-dihydroxyl-6-(pyridin-3-yl oxygen base)-isoquinoline-3-carboxylic acid butyl ester and 1, the regional isomerism mixture of 4-dihydroxyl-7-(pyridin-3-yl oxygen base)-isoquinoline-3-carboxylic acid butyl ester synthesizes.This regional isomer does not separate; MS-(+)-ion: M+1=373.01.
G) 4-hydroxyl-6-(pyridin-3-yl oxygen base)-isoquinoline-3-carboxylic acid butyl ester (A) and 4-hydroxyl-7-(pyridin-3-yl oxygen base)-isoquinoline-3-carboxylic acid butyl ester (B)
Be similar to instance D-7f), synthesize by the regional isomerism mixture of 1-chloro-4-hydroxyl-6-(pyridin-3-yl oxygen base)-isoquinoline-3-carboxylic acid butyl ester and 1-chloro-4-hydroxyl-7-(pyridin-3-yl oxygen base)-isoquinoline-3-carboxylic acid butyl ester.On silica gel, use CH through flash column chromatography 2C1 2: EtOAc (90: 10 to 80: 20) wash-out comes the separated region isomer.Evaporate first fraction and obtain B; MS-(+)-ion: M+1=339.09.Evaporate second fraction and obtain A; MS-(+)-ion: M+1=339.10.
H) { [4-hydroxyl-6-(pyridin-3-yl oxygen base)-isoquinoline 99.9-3-carbonyl]-amino }-acetate
Be similar to instance D-1g), synthetic by 4-hydroxyl-6-(pyridin-3-yl oxygen base)-isoquinoline-3-carboxylic acid butyl ester; MS-(+)-ion: M+1=340.06.
Instance D-67
{ [4-hydroxyl-7-(pyridin-3-yl oxygen base)-isoquinoline 99.9-3-carbonyl]-amino }-acetate
Be similar to instance D-1g), synthetic by 4-hydroxyl-7-(pyridin-3-yl oxygen base)-isoquinoline-3-carboxylic acid butyl ester; MS-(+)-ion: M+1=340.06.
Instance D-68
[(1-chloro-4-methoxyl group-isoquinoline 99.9-3-carbonyl)-amino]-acetate
A) [(1-chloro-4-methoxyl group-isoquinoline 99.9-3-carbonyl)-amino]-methyl acetate
[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate (56mg, 0.2mmol under agitation refluxes; Can be according to people's such as Weidmann USP 6,093,730,10/1998 obtains), Me 2SO 4(57 μ l, 0.6mmol), KHCO 3(306mg, 3mmol) and the mixture 48h of acetone (4ml).After this evaporating solvent and water (4ml) is added in the resistates.(3 * 20ml) extract this mixture with EtOAc.Via MgSO 4The dry organic phase that merges is also evaporated to produce brown oil in a vacuum.On silica gel, use hexane: EtOAc=7 through flash column chromatography: 3 come purifying as elutriant, produce the title compound (21mg) that is light yellow oil; MS-(+)-ion: M+1=308.9.
B) [(1-chloro-4-methoxyl group-isoquinoline 99.9-3-carbonyl)-amino]-acetate
Stir at ambient temperature [(1-chloro-4-methoxyl group-isoquinoline 99.9-3-carbonyl)-amino]-methyl acetate (21mg, 0.07mmol), KOH (23mg, 0.35mmol) and the mixture 3h of EtOH (1ml).Follow evaporating solvent in a vacuum.Resistates is dissolved in the water (2ml) and through adding the 1N HCl aqueous solution pH of this solution is adjusted into 2-3.(4 * 10ml) extract this mixture with EtOAc.Via MgSO 4The dry organic phase that merges is also evaporated the title compound (18mg) that is slight yellow solid with generation in a vacuum; MS-(+)-ion: M+1=295.0.
Instance D-69
[(1-chloro-4-oxyethyl group-isoquinoline 99.9-3-carbonyl)-amino]-acetate
A) [(1-chloro-4-oxyethyl group-isoquinoline 99.9-3-carbonyl)-amino]-ETHYLE ACETATE
[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate (56mg, 0.2mmol under agitation refluxes; Can be according to people's such as Weidmann USP 6,093,730,10/1998 obtains), Et 2SO 4(59 μ l, 0.44mmol), KHCO 3(306mg, 3mmol) and Et 2The mixture 18h of CO (3ml).Then evaporating solvent and water (4ml) is added in the resistates.This mixture of vigorous stirring 5min.Filter then.Be dissolved among the EtOAc filter cake and via MgSO 4Dry this solution.Concentrate this solution in a vacuum.The gained brown solid is dissolved among the EtOAc (0.5ml) and adds hexane.Store this mixture 14h at ambient temperature, then solvent is poured out from formed throw out.The dried in vacuum throw out is with the generation crystalline title compound (8mg) that is white in color; MS-(+)-ion: M+1=337.0.
B) [(1-chloro-4-oxyethyl group-isoquinoline 99.9-3-carbonyl)-amino]-acetate
Be similar to instance D-68b), synthetic by [(1-chloro-4-oxyethyl group-isoquinoline 99.9-3-carbonyl)-amino] ETHYLE ACETATE; MS-(+)-ion: M+1=309.0.
Instance D-70
{ [4-hydroxyl-1-methoxyl group-isoquinoline 99.9-3-carbonyl]-amino }-acetate
A) 4-benzyloxy-1-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
At ambient temperature with 1,4-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester (26.13g, 100mmol; Instance D-20b), PhCH 2Br (18.2ml, 150mmol), (100mmol) mixture stirs 48h to MeONa for 0.5M among the MeOH, 200ml.Then evaporating solvent and EtOAc (100ml) is added in the resistates.This mixture of vigorous stirring 10min.Filter then.With the 2.5N NaOH aqueous solution (2 * 100ml) with the 2N HCl aqueous solution (1 * 100ml) cleans filtrate.Via MgSO 4Dry organic phase and evaporation in a vacuum.Make resistates recrystallize from MeOH (500ml)/water (300ml).On silica gel, use hexane: EtOAc: NEt through flash column chromatography 3=65: as elutriant be further purified gained yellow solid to produce 10.8g yellow solid at 30: 5.On silica gel, use hexane: EtOAc: NEt through flash column chromatography 3=75: as elutriant be further purified 2g this material to produce title compound that 1.57g be slight yellow solid at 20: 5; 1H NMR (CDC1 3): δ=8.88 (bs, 1H), 8.46 (d, 1H), 8.42 (d, 1H), 7.26-7.96 (m, 7H), 5.06 (s, 2H), 4.38 (t, 2H), 1.69 (m, 2H), 1.37 (m, 2H), 0.91 (t, 3H).
B) 4-benzyloxy-1-methoxyl group-isoquinoline-3-carboxylic acid butyl ester
At ambient temperature with 4-benzyloxy-1-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (1 equivalent), Me 3OBF 4(6 equivalent), KHCO 3(14 equivalent) and CH 2C1 2The mixture of (10ml/mmol 4-benzyloxy-1-hydroxyl-isoquinoline-3-carboxylic acid butyl ester) stirs 24h.Then add water (10ml/mmol) and use CH 2Cl 2(40ml/mmol) extract this mixture.Separate organic phase, via MgSO 4Drying is also evaporated to produce little yellow solid in a vacuum.On silica gel, use hexane: EtOAc=85 through flash column chromatography: 15 come the purifying crude product as elutriant.Evaporate first fraction and be the title compound of colorless oil with generation, productive rate is 20%; 1H NMR (CDCl 3): δ=8.21-8.25 (m, 1H), 8.05-8.09 (m, 1H), 7.33-7.73 (m, 7H), 5.13 (s, 2H), 4.38 (t, 2H), 4.16 (s, 3H), 1.69 (m, 2H), 1.37 (m, 2H), 0.94 (t, 3H).
C) 4-hydroxyl-1-methoxyl group-isoquinoline-3-carboxylic acid butyl ester
At H 2Under environmental stress and temperature, stir under-the atmosphere 4-benzyloxy-1-methoxyl group-isoquinoline-3-carboxylic acid butyl ester (164mg, 0.45mmol), the mixture 16h of Pd/C (50mg, 10 weight %Pd) and EtOAc (15ml).Then filter this mixture through Celite pad.Thoroughly clean zeyssatite and filter cake and concentrate in a vacuum with EtOAc and merge organic phase with the generation solid title compound (115mg) that is white in color; 1HNMR (CDCl 3): δ=11.48 (s, 1H), 8.27-8.32 (m, 1H), 8.17-8.21 (m, 1H), 7.65-7.78 (m, 2H), 4.43 (t, 2H), 4.10 (s, 3H), 1.87 (m, 2H), 1.54 (m, 2H), 1.02 (t, 3H).
D) [(4-hydroxyl-1-methoxyl group-isoquinoline 99.9-3-carbonyl)-amino]-acetate
Be similar to instance D-1g), synthetic by 4-hydroxyl-1-methoxyl group-isoquinoline-3-carboxylic acid butyl ester; MS-(-)-ion: M-1=275.0.
Instance D-71
[(1-oxyethyl group-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
A) 1-oxyethyl group-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Stir 4-benzyloxy-1-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (422mg, 1.2mmol, instance D-70a), KHCO at ambient temperature 3(2.22g, 22mmol) with 1M at CH 2Cl 2(10ml, the Et in 10mmol) 3OBF 4Mixture 16h and then under agitation refluxed 3 days.According to TLC, 4-benzyloxy-1-hydroxyl-isoquinoline-3-carboxylic acid butyl ester does not react under these conditions.Therefore, add other KHCO 3(2.22g, 22mmol) with 1M at CH 2Cl 2(10ml, the Et in 10mmol) 3OBF 4, and this mixture is concentrated in a vacuum.Subsequently, add 1,2-ethylene dichloride (10ml) and this mixture 16h that under agitation refluxes.Follow evaporating solvent in a vacuum.Water (25ml) is added in the resistates and (2 * 50ml) extract this mixture with EtOAc.Via MgSO 4The dry organic phase that merges is also evaporated to produce little yellow solid (374mg) in a vacuum.On silica gel, use hexane: EtOAc=85 through flash column chromatography: 15 come purifying as elutriant, obtain little yellow oil (104mg).Reuse hexane: EtOAc=99: 2 and 99: 1 subsequently chromatography purifications as elutriant, obtain being the title compound (60mg) of water white oil; 1H NMR (CDC1 3): δ=11.45 (s, 1H), 8.20-8.32 (m, 2H), 7.64-7.78 (m, 2H), 4.38-4.59 (m, 4H), 1.84 (m, 2H), 1.54 (m, 5H), 1.01 (t, 3H).
B) [(1-oxyethyl group-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
Be similar to instance D-1g), synthetic by 1-oxyethyl group-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester; MS-(+)-ion: M+1=291.0.
Instance D-72
[(4-oxyethyl group-1-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
A) [(1-oxygen-3-phenyl-1H-indenes-2-carbonyl)-amino]-methyl acetate
1-oxygen-3-phenyl-lH-indenes-2-formic acid (2.13g, 8.5mmol under agitation refluxes; Can according to people such as M.R.Barvian 1997 the 7th phases " bioorganic chemistry and pharmaceutical chemistry communication " (Bioorg.Med.Chem.Lett.) description of 2903-2908 page or leaf obtain) and SOC1 2Mixture 15min (17ml).Then evaporate excessive SOC1 in a vacuum 2Resistates is dissolved in anhydrous CH 2Cl 2Also concentrate this solution (20ml) subsequently in a vacuum once more to remove last micro-SOCl 2Resistates is dissolved in anhydrous CH 2Cl 2(20ml).With this solution of ice bath cooling, (1.27g 10mmol) also adds NEt subsequently under agitation to add glycine methyl ester hydrochloride then 3(3.52ml, 25mmol dropwise add).Then remove ice bath and continue to stir 45min at ambient temperature, then enriched mixture in a vacuum.Be added in the resistates water (10ml) and the 2N HCl aqueous solution (15ml) and (1 * 70ml) extracts this mixture with ETHYLE ACETATE.Via MgSO 4Dry organic phase is also evaporated to produce safran solid (2.77g) in a vacuum.On silica gel, use hexane: EtOAc=2 through flash column chromatography: 1 comes purifying as elutriant, produces to be safran solid title compound (2.11g); MS-(+)-ion: M+1=322.0.
B) [(4-acetoxyl group-1-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-methyl acetate
(1.864g 5.8mmol) is dissolved in dense H with [(1-oxygen-3-phenyl-lH-indenes-2-carbonyl)-amino]-methyl acetate with 50 to 60 ℃ 2SO 4(16ml) and in the mixture of Glacial acetic acid min. 99.5 (16ml).Then NaN is added in gradation under agitation 3(985mg 15mmol) makes temperature be no more than 60 ℃.Then continue to stir 30min again, then this mixture is annotated on ice (200g) at 50 to 60 ℃.Through adding dense NH 3(55ml is D=0.89g/ml) with the alkalization of the mixture of gained and use CH for the aqueous solution 2Cl 2(2 * 100ml) extractions.Via MgSO 4The dry organic phase that merges is also then filtered through silica gel.Filtrate is abandoned.Clean silica gel with EtOAc (about 400ml).Concentrate gained solution in a vacuum to produce black oil (250mg).On silica gel, use EtOAc and then use EtOAc through flash column chromatography: hexane=7: 3 is further purified to produce as elutriant and is pale brown look solid title compound (19mg); 1H NMR (CDCl 3): δ=7.11-7.98 (m), 3.75 (d, 2H), 3.68 (s, 1H), 2.19 (s, 3H).
C) [(4-acetoxyl group-1-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
(3.8mg, 0.01mmol) mixture with the 6N HCl aqueous solution (1ml) stirs 16h, then through adding dense NaHCO with [(4-acetoxyl group-1-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-methyl acetate at ambient temperature 3The aqueous solution is adjusted into about 8 with the pH value of this solution.(2 * 10ml) clean this solution, then through adding the 2N HCl aqueous solution with its acidifying with EtOAc.(2 * 10ml) extract this mixture to use EtOAc subsequently.Via MgSO 4The dry organic phase that merges is also evaporated the title compound (1.9mg) that is yellow oily with generation in a vacuum; MS-(+)-ion: M+1=364.9.
Instance D-73
[(4-hydroxyl-1-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
A) 4-hydroxyl-1-phenyl-isoquinoline-3-carboxylic acid ethyl ester
Under agitation with 4-acetoxyl group-1-phenyl-isoquinoline-3-carboxylic acid ethyl ester (671mg, 2mmol; Can according to people such as D.A.Walsh 1978 the 21st phases " description in the pharmaceutical chemistry journal 582-585 page or leaf obtains), n-BuOH (60ml) and dense H 2SO 4Mixture backflow 4h (1.7ml) under agitation is added into dense NaHCO with reaction mixture then 3In the aqueous solution (60ml).Then add EtOAc (120ml) and this mixture of vigorous stirring 15min.Separate organic phase subsequently, via MgSO 4Dry and concentrated in a vacuum.On silica gel, use hexane: EtOAc=95 through flash column chromatography: 5 come the purifying resistates as elutriant, produce solid title compound (126mg); 1H NMR (CDCl 3): δ=11.96 (s, 1H), 8.44-8.49 (m, 1H), 8.01-8.05 (m, 1H), 7.43-7.80 (m, 7H), 4.56 (q, 2H), 1.49 (t, 3H).
B) [(4-hydroxyl-1-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
Be similar to instance D-1g), synthetic by 4-hydroxyl-1-phenyl-isoquinoline-3-carboxylic acid ethyl ester; MS-(+)-ion: M+1=323.1.
Instance D-74
[(1-oxyethyl group-4-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
A) 1-chloro-4-phenyl-isoquinoline-3-carboxylic acid ethyl ester
Under agitation with 1-hydroxy-4-phenyl-isoquinoline-3-carboxylic acid ethyl ester (1.17g, 4mmol; Can obtain in the description of 1962 the 52nd phase Ann.Chim. (Rome) 112-120 pages or leaves according to people such as A.Marsili) and dense POCl 3Mixture backflow 1h (10ml).Then concentrate this mixture in a vacuum.Resistates is dissolved among the EtOAc (50ml), adds dense NaHCO 3The aqueous solution (40ml) and this mixture of vigorous stirring 1h.Separate organic phase subsequently.Via MgSO 4Dry and the concentrated in a vacuum title compound (1.20g) that is little yellow solid with generation; MS-(+)-ion: M+1=312.0.
B) [(1-chloro-4-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-methyl acetate
Under agitation with 1-chloro-4-phenyl-isoquinoline-3-carboxylic acid ethyl ester (1.184g, 3.8mmol), the 2N NaOH aqueous solution (15ml, 30mmol) and the mixture backflow 2.5h of EtOH (15ml).Then this mixture is concentrated into 1/2 of its volume.Subsequently, through adding dense this solution of HCl acidifying and extracting gained suspension-s with EtOAc (2x 50ml).Via MgSO 4The dry organic phase that merges is also evaporated to produce little yellow solid (1.018g) in a vacuum.With SOCl 2(7ml) be added in this little yellow solid of 996mg also under agitation with this mixture backflow 1h.Then with excessive SOCl 2Evaporation in a vacuum.Resistates is dissolved in anhydrous CH 2Cl 2Also concentrate this solution (10ml) subsequently in a vacuum once more to remove last micro-SOCl 2Resistates is dissolved in anhydrous CH 2Cl 2(8ml).With this solution of ice bath cooling, (507mg 4mmol) also adds NEt subsequently under agitation to add glycine methyl ester hydrochloride then 3(1.55ml, 11mmol dropwise add).Then remove ice bath and continue to stir 1h at ambient temperature, concentrate this mixture then in a vacuum.Water (15ml) is added in the resistates and (1 * 50ml) extracts this mixture with EtOAc.Via MgSO 4Dry organic phase is also evaporated to produce pale brown look solid (1.07g) in a vacuum.Recrystallize produces the title compound (430mg) that is slight yellow solid from MeOH (30ml)/water (10ml); MS-(+)-ion: M+1=355.0.
C) [(1-oxyethyl group-4-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
Stir at ambient temperature [(1-chloro-4-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-methyl acetate (177mg, 0.5mmol), KOH (325mg, 5mmol) and the mixture 90min of EtOH (10ml), evaporating solvent in a vacuum then.Resistates is dissolved in the water (10ml).The dense HCl aqueous solution comes this solution of acidifying and (2 * 15ml) extract with EtOAc through adding.Via MgSO 4Dry organic phase and the concentrated in a vacuum title compound (169mg) that is slight yellow solid with generation of merging; MS-(+)-ion: M+1=351.0.
Instance D-75
[(1-chloro-4-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
Mixture with [(1-chloro-4-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-methyl acetate (50mg, 0.14mmol, instance D-74b) and the 6N HCl aqueous solution stirred 11 days at ambient temperature, then through adding dense NaHCO 3The aqueous solution this solution that neutralizes.Extract this mixture with EtOAc (50ml).Via MgSO 4Dry organic phase also concentrates with the generation solid title compound (35mg) that is white in color in a vacuum; MS-(+)-ion: M+1=341.0.
Instance D-76
[(4-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
A) [(4-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-methyl acetate
At H 2Under environmental stress and temperature, stir [(1-chloro-4-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-methyl acetate (177mg under-the atmosphere; 0.5mmol; Instance D-74b), Pd/C (50mg; 10 weight %Pd), sodium acetate (49mg, 0.6mmol), the mixture 2h of MeOH (10ml) and EtOAc (5ml).Then filter this mixture through Celite pad.Thoroughly clean zeyssatite and filter cake and concentrate the merging organic phase in a vacuum with EtOAc.With dense NaHCO 3The aqueous solution (10ml) is added in the resistates and (2 * 15ml) extract this mixture with EtOAc.Via MgSO 4Dry organic phase and the concentrated in a vacuum title compound (154mg) that is no coloring agent with generation of merging; MS-(+)-ion: M+1=321.0.
B) [(4-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
Stir at ambient temperature [(4-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-methyl acetate (144mg, 0.45mmol), KOH (325mg, 5mmol) and the mixture 18h of EtOH (10ml), evaporating solvent in a vacuum then.Resistates is dissolved in the water.Through adding the dense HCl aqueous solution pH value of this solution is adjusted into 3-4.Then (2 * 25ml) extract this solution with EtOAc.Via MgSO 4Dry organic phase and the concentrated in a vacuum title compound (127mg) that is little yellow solid with generation of merging; MS-(+)-ion: M+1=307.1.
Instance D-77
[(4-hydroxyl-1-methyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
A) 1-bromo-4-hydroxyl-isoquinoline-3-carboxylic acid
Under agitation with 1-bromo-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (8.18g, 25mmol; Instance D-28a), the 2N NaOH aqueous solution (80ml, 160mmol) and the mixture backflow 2h of EtOH (80ml).Then concentrate 1/2 of this solution to its volume in a vacuum, water (200ml) dilution also passes through to add dense HCl acidified aqueous solution.Make the vacuum filtration of gained suspension-s after stirring 1h at ambient temperature.Water thoroughly clean filter cake in a vacuum in 75 ℃ of dryings with the generation solid title compound (6.10g) that is white in color; 1HNMR (DMSO-d 6): δ=8.30-8.37 (m, 1H), 8.16-8.22 (m, 1H), 7.93-8.03 (m, 2H).
B) 4-hydroxyl-1-methyl-isoquinoline-3-carboxylic acid methyl esters
Under agitation (4ml, 10mmol) solution slowly is added into l-bromo-4-hydroxyl-isoquinoline-3-carboxylic acid (670mg is in anhydrous THF (100ml) solution 2.5mmol) in-78 ℃ of hexanes with 2.5M n-BuLi.After stirring 5min again, add MeI (316 μ l, 5mmol).10min is stirred in continuation again under-78 ℃, add the water (50ml) and the 2N HCl aqueous solution (6ml) then.Under agitation make this mixture temperature to envrionment temperature and then be concentrated into about 1/2 of its volume in a vacuum.With the throw out sucking-off of gained, water cleans, in a vacuum in 80 ℃ of dryings and from EtOH recrystallize produce light brown yellow solid (141mg).The above-mentioned light brown yellow solid of the 102mg that under agitation refluxes, Me 2SO 4(48ml, 0.5mmol), KHCO 3(1.0g, 10mmol) and the mixture 15h of acetone (10ml).Then concentrate this mixture in a vacuum.Water (20ml) is added in the resistates and (3 * 20ml) extract this mixture with EtOAc.Via MgSO 4Dry merging organic phase also concentrates in a vacuum and is pale brown look solid title compound with generation; 1H NMR (CDCl 3): δ=11.66 (s, 1H), 8.39-8.44 (m, 1H), 8.02-8.09 (m, 1H), 7.74-7.81 (m, 2H), 4.08 (s, 3H), 2.90 (s, 3H).
C) [(4-hydroxyl-1-methyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
Be similar to instance D-1g), synthetic by 4-hydroxyl-1-methyl-isoquinoline-3-carboxylic acid methyl esters; MS-(-)-ion: M-1=259.0.
Instance D-78
[(4-hydroxyl-1-methoxymethyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
A) 4-benzyloxy-1-methoxymethyl-isoquinoline-3-carboxylic acid benzyl ester
Under agitation in-78 ℃ of hexanes with 2.5M n-BuLi (4ml, 10mmol) solution slowly is added into l-bromo-4-hydroxyl-isoquinoline-3-carboxylic acid (670mg, 2.5mmol; Instance D-77a) in anhydrous THF (100ml) solution.After stirring 5min again, add MeOCH 2I (446 μ l, 5mmol).5min is stirred in continuation again under-78 ℃, add the water (50ml) and the 6N HCl aqueous solution (2ml) then.Under agitation make this mixture temperature to envrionment temperature and then be concentrated into about 1/3 of its volume in a vacuum and also extract with EtOAc (50ml).Water (10ml) solution with Sodium Pyrosulfite (0.5g) cleans organic phase, then via MgSO 4Dry and concentrated in a vacuum to produce little yellow solid (432mg).
The above-mentioned little yellow solid of the 429mg that under agitation refluxes, bromotoluene (0.6ml, 5mmol), K 2CO 3(2.07g, 15mmol) and the mixture of acetone (40ml) 2.5 days.Then concentrate this mixture in a vacuum.Water (40ml) is added in the resistates and extracts this mixture with EtOAc (50ml).Via MgSO 4Dry organic phase also concentrates to produce brown oil in a vacuum.On silica gel, use hexane: EtOAc=6 through flash column chromatography: 4 come purifying as elutriant, produce the title compound (201mg) that is yellow oil; MS-(+)-ion: M+1=414.1.
B) 4-benzyloxy-1-methoxymethyl-isoquinoline-3-carboxylic acid
Stir at ambient temperature 4-benzyloxy-1-methoxymethyl-isoquinoline-3-carboxylic acid benzyl ester (198mg, 0.48mmol), KOH (325mg, 5mmol) and the mixture 18h of EtOH (10ml), evaporating solvent in a vacuum then.Water (25ml) is added in the resistates and uses Et 2(2 * 25ml) clean this mixture to O.Then come this solution of acidifying also to extract with EtOAc (25ml) through adding the 6N HCl aqueous solution.Via MgSO 4Dry organic phase also concentrates the title compound (140mg) that is yellow oil with generation in a vacuum; MS-(+)-ion: M+1=324.1.
C) [(4-benzyloxy-1-methoxymethyl-isoquinoline 99.9-3-carbonyl)-amino]-jasmal
Under agitation with ClCO 2IBu (52 μ l, 0.39mmol) be added into ice bath refrigerative 4-benzyloxy-1-methoxymethyl-isoquinoline-3-carboxylic acid (120mg, 0.37mmol), NEt 3(109 μ l, 0.78mmol) and CH 2Cl 2In the mixture (7ml).After stirring 15min, (79mg 0.39mmol) and in addition stirs this mixture 15min again, removes ice bath then to add glycine benzyl hydrochloride.Then continue to stir again at ambient temperature 1.5h.Concentrate this mixture subsequently in a vacuum.Water (10ml) and several 6N HCl aqueous solution are added in the resistates.Extract this mixture with EtOAc (15ml).Via MgSO 4Dry organic phase also concentrates to produce little yellow glue in a vacuum.On silica gel, use hexane: EtOAc=7 through flash column chromatography: 3 come purifying as elutriant, produce the title compound (141mg) that is yellow oil; MS-(+)-ion: M+1=471.1.
D) [(4-hydroxyl-1-methoxymethyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
At H 2Under environmental stress and temperature, stir under-the atmosphere [(4-benzyloxy-1-methoxymethyl-isoquinoline 99.9-3-carbonyl)-amino]-jasmal (134mg, 0.285mmol), the mixture 18h of Pd/C (100mg, 10 weight %Pd) and EtOAc (10ml).Then filter this mixture through Celite pad.Thoroughly clean zeyssatite and filter cake and concentrated in a vacuum merging organic phase with EtOAc and be pale brown look solid title compound (74mg) with generation; MS-(-)-ion: M-1=289.2.
Instance D-79
[(1-dimethylamino formyl radical-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
A) 4-benzyloxy-1-dimethylamino formyl radical-isoquinoline-3-carboxylic acid benzyl ester
Under agitation in-78 ℃ of hexanes with 2.5M n-BuLi (4ml, 10mmol) solution slowly is added into l-bromo-4-hydroxyl-isoquinoline-3-carboxylic acid (670mg, 2.5mmol; Instance D-77a) in anhydrous THF (100ml) solution.After stirring 5min again, add ClCONMe 2(468 μ l, 5mmol).5min is stirred in continuation again under-78 ℃, add the water (50ml) and the 6N HCl aqueous solution (2ml) then.Under agitation make this mixture temperature to envrionment temperature and then be concentrated in a vacuum its volume about 1/3 and with EtOAc (2 * 50ml) extract.Via MgSO 4The dry organic phase and concentrated in a vacuum that merges to produce yellow solid (501mg).Under agitation reflux the above-mentioned yellow solid of 492mg, bromotoluene (0.6ml, 5mmol), K 2CO 3(2.07g, 15mmol) and the mixture of acetone (40ml) 2.5 days.Concentrate this mixture subsequently in a vacuum.Water (20ml) is added in the resistates and extracts this mixture with EtOAc (50ml).Via MgSO 4Dry organic phase also concentrates to produce brown oil in a vacuum.On silica gel, use hexane: EtOAc=6 through flash column chromatography: 4 come purifying as elutriant, produce the title compound (311mg) that is yellow oil; MS-(+)-ion: M+1=441.1.
B) 4-benzyloxy-1-dimethylamino formyl radical-isoquinoline-3-carboxylic acid
Stir at ambient temperature 4-benzyloxy-1-dimethylamino formyl radical-isoquinoline-3-carboxylic acid benzyl ester (308mg, 0.7mmol), KOH (325mg, 5mmol) and the mixture 18h of EtOH (10ml), evaporating solvent in a vacuum then.Water (25ml) is added in the resistates and uses Et 2(2 * 25ml) clean this mixture to O.Then the 6N HCl aqueous solution comes this solution of acidifying and (2 * 25ml) extract with EtOAc through adding.Via MgSO 4Dry organic phase and the concentrated in a vacuum title compound (220mg) that is little yellow glue with generation of merging; MS-(+)-ion: M+1=351.0.
C) [(4-benzyloxy-1-dimethylamino formyl radical-isoquinoline 99.9-3-carbonyl)-amino]-jasmal
Under agitation with ClCO 2IBu (83 μ l, 0.63mmol) be added into ice bath refrigerative 4-benzyloxy-1-dimethylamino formyl radical-isoquinoline-3-carboxylic acid (210mg, 0.6mmol), NEt 3(175 μ l, 1.25mmol) and CH 2Cl 2In the mixture (12ml).After stirring 15min, (127mg 0.63mmol) and in addition stirs this mixture 15min again, removes ice bath then to add glycine benzyl hydrochloride.Then continue to stir again at ambient temperature 1.5h.Concentrate this mixture subsequently in a vacuum.Water (10ml) and several 6N HCl aqueous solution are added in the resistates.Extract this mixture with EtOAc (15ml).Via MgSO 4Dry organic phase also concentrates to produce little yellow glue in a vacuum.On silica gel, use hexane: EtOAc=7 through flash column chromatography: 3 come purifying as elutriant, produce the title compound (211mg) that is slight yellow glue; MS-(+)-ion: M+1=498.1.
D) [(1-dimethylamino formyl radical-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
At H 2Under environmental stress and temperature, stir [(4-benzyloxy-1-dimethylamino formyl radical-isoquinoline 99.9-3-carbonyl)-amino]-jasmal (209mg under-the atmosphere; 0.42mmol), the mixture 18h of Pd/C (100mg, 10 weight %Pd), EtOAc (10ml) and MeOH (50ml).Then filter this mixture through Celite pad.Thoroughly clean zeyssatite and filter cake and concentrate the merging organic phase is brown solid with generation title compound (122mg) in a vacuum with EtOAc; MS-(-)-ion: M-1=316.1.
Instance D-80
[(4-hydroxyl-1-methyl-6-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-acetate
A) 1-bromo-4-hydroxyl-6-phenoxy-isoquinoline-3-carboxylic acid
Be similar to instance D-77a), synthetic by 1-bromo-4-hydroxyl-6-phenoxy-isoquinoline-3-carboxylic acid butyl ester (instance D-77a); 1H NMR (DMSO-d 6): δ=8.20 (d, 1H), 7.21-7.74 (m, 7H).
B) 4-benzyloxy-1-methyl-6-phenoxy-isoquinoline-3-carboxylic acid benzyl ester
Under agitation (3.2ml, 8mmol) solution slowly is added into l-bromo-4-hydroxyl-6-phenoxy-isoquinoline-3-carboxylic acid (721mg is in anhydrous THF (100ml) solution 2mmol) in-78 ℃ of hexanes with 2.5M n-BuLi.After stirring 10min again, dropwise add MeI (253 μ l, 4mmol).15min is stirred in continuation again under-78 ℃, add the water (50ml) and the 2N HCl aqueous solution (5ml) then.Under agitation make this mixture temperature to envrionment temperature and then be concentrated into about 1/3 of its volume in a vacuum.The formed throw out of sucking-off, water cleaning and dried in vacuum are to produce pale brown look solid (758mg).The above-mentioned pale brown look solid of the 738mg that under agitation refluxes, bromotoluene (1.0ml, 8mmol), K 2CO 3(2.76g, 20mmol) and the mixture of acetone (50ml) 3 days.Then concentrate this mixture in a vacuum.Water (30ml) is added in the resistates and extracts this mixture with EtOAc (50ml).Via MgSO 4Dry organic phase also concentrates to produce little yellow oil in a vacuum.On silica gel, use hexane: EtOAc=8 through flash column chromatography: 2 come purifying as elutriant, produce pale brown look solid.Recrystallize produces the title compound (172mg) that is slight yellow solid from MeOH; MS-(+)-ion: M+1=476.1.
C) 4-benzyloxy-1-methyl-6-phenoxy-isoquinoline-3-carboxylic acid
Be similar to instance D-78b), synthetic by 4-benzyloxy-1-methyl-6-phenoxy-isoquinoline-3-carboxylic acid benzyl ester; MS-(+)-ion: M+1=386.1.
D) [(4-benzyloxy-1-methyl-6-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-jasmal
Be similar to instance D-78c), synthetic by 4-benzyloxy-1-methyl-6-phenoxy-isoquinoline-3-carboxylic acid; MS-(+)-ion: M+1=533.0.
E) [(4-hydroxyl-1-methyl-6-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-acetate
Be similar to instance D-78d), synthetic by [(4-benzyloxy-1-methyl-6-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-jasmal; MS-(+)-ion: M+1=353.1.
Instance D-81
[(4-hydroxyl-1-methyl-7-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-acetate
A) 1-bromo-4-hydroxyl-7-phenoxy-isoquinoline-3-carboxylic acid
Be similar to instance D-77a), synthetic by 1-bromo-4-hydroxyl-7-phenoxy-isoquinoline-3-carboxylic acid butyl ester (instance D-7e); MS-(+)-ion: M+1=359.9.
B) 4-benzyloxy-1-methyl-7-phenoxy-isoquinoline-3-carboxylic acid benzyl ester
Be similar to instance D-78a), synthetic by MeI and 1-bromo-4-hydroxyl-7-phenoxy-isoquinoline-3-carboxylic acid; MS-(+)-ion: M+1=476.1.
C) 4-benzyloxy-1-methyl-7-phenoxy-isoquinoline-3-carboxylic acid
Be similar to instance D-78b), synthetic by 4-benzyloxy-1-methyl-7-phenoxy-isoquinoline-3-carboxylic acid benzyl ester; MS-(+)-ion: M+1=386.0.
D) [(4-benzyloxy-1-methyl-7-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-jasmal
Be similar to instance D-78c), synthetic by 4-benzyloxy-1-methyl-7-phenoxy-isoquinoline-3-carboxylic acid; MS-(+)-ion: M+1=533.0.
E) [(4-hydroxyl-1-methyl-7-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-acetate
Be similar to instance D-78d), synthetic by [(4-benzyloxy-1-methyl-7-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-jasmal; MS-(-)-ion: M-1=351.1.
Instance D-82
[(4-benzyloxy-1-methyl-7-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-acetate
Stir [(4-benzyloxy-1-methyl-7-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-jasmal (160mg, 0.3mmol at ambient temperature; Instance D-81d), KOH (325mg, 5mmol) and the mixture 18h of EtOH (10ml), evaporating solvent in a vacuum then.Water (5ml) is added in the resistates and uses Et 2(2 * 20ml) clean this mixture to O.Then the 6N HCl aqueous solution comes this solution of acidifying and (2 * 20ml) extract with EtOAc through adding.Via MgSO 4Dry organic phase and the concentrated in a vacuum title compound (93mg) that is pale brown coloring agent with generation of merging; MS-(+)-ion: M+1=443.0.
Instance D-83
[(4-oxyethyl group-1-methyl-7-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-acetate
A) 4-oxyethyl group-1-methyl-7-phenoxy-isoquinoline-3-carboxylic acid ethyl ester
Under agitation (3.2ml, 8mmol) solution slowly is added in anhydrous THF (100ml) solution of l-bromo-4-hydroxyl-7-phenoxy-isoquinoline-3-carboxylic acid (721mg, 2mmol, instance D-81a) in-78 ℃ of hexanes with 2.5M n-BuLi.After stirring 5min again, dropwise add MeI (253 μ l, 4mmol).15min is stirred in continuation again under-78 ℃, add the water (100ml) and the 2N HCl aqueous solution (5ml) then.Under agitation make this mixture temperature to envrionment temperature, then be concentrated into about 1/2 of its volume in a vacuum and also extract with EtOAc (300ml).Via MgSO 4Dry organic phase also concentrates to produce safran solid (462mg) in a vacuum.The above-mentioned safran solid of the 440mg that under agitation refluxes, EtI (0.61ml, 7.5mmol), K 2CO 3(3.0g, 21.7mmol) and the mixture of acetone (45ml) 16 days.Then concentrate this mixture in a vacuum.Water (30ml) is added in the resistates and (2 * 50ml) extract this mixture with EtOAc.Via MgSO 4The dry organic phase and concentrated in a vacuum that merges to produce brown oil.On silica gel, use hexane: EtOAc=8 through flash column chromatography: 2 come purifying as elutriant, produce the title compound (34mg) that is little yellow oil; 1H NMR (CDCl 3): δ=8.22 (d, 1H), 7.07-7.50 (m, 7H), 4.50 (q, 2H), 4.20 (q, 2H), 2.80 (s, 3H), 1.43-1.58 (m, 6H).
B) 4-oxyethyl group-1-methyl-7-phenoxy-isoquinoline-3-carboxylic acid
Be similar to instance D-78b), synthetic by 4-oxyethyl group-1-methyl-7-phenoxy-isoquinoline-3-carboxylic acid ethyl ester; MS-(+)-ion: M+1=324.1.
C) [(4-oxyethyl group-1-methyl-7-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-tert.-butyl acetate
Be similar to instance D-78c), synthetic by glycine tert-butyl hydrochloride and 4-oxyethyl group-1-methyl-7-phenoxy-isoquinoline-3-carboxylic acid; MS-(+)-ion: M+1=437.1.
D) [(4-oxyethyl group-1-methyl-7-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-acetate
Stir at ambient temperature [(4-oxyethyl group-1-methyl-7-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-tert.-butyl acetate (14mg, 0.032mmol) and the mixture 3h of trifluoroacetic acid (2ml).Then concentrate this mixture in a vacuum and resistates is dissolved among the EtOH (5ml).Evaporating mixture is the title compound (12mg) of little yellow solid with generation in a vacuum; MS-(-)-ion: M-1=381.1.
Instance D-84
[(1-dimethylamino formyl radical-4-hydroxyl-7-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-acetate
A) 4-benzyloxy-1-dimethylamino formyl radical-7-phenoxy-isoquinoline-3-carboxylic acid benzyl ester
Be similar to instance D-79a, synthesize by 1-bromo-4-hydroxyl-7-phenoxy-isoquinoline-3-carboxylic acid (instance D-81a) and (use 6 equivalent ClCONMe 2, finishing to add ClCONMe 2Afterwards, at-78 ℃ of following stirred reaction mixture 75min, add water and HCl then); MS-(+)-ion: M+1=533.2.
B) 4-benzyloxy-1-dimethylamino formyl radical-7-phenoxy-isoquinoline-3-carboxylic acid
Be similar to instance D-79b), synthetic by 4-benzyloxy-1-dimethylamino formyl radical-7-phenoxy-isoquinoline-3-carboxylic acid benzyl ester; MS-(-)-ion: M-1=441.1.
C) [(4-benzyloxy-1-dimethylamino formyl radical-7-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-jasmal
Be similar to instance D-79c), synthetic by 4-benzyloxy-1-dimethylamino formyl radical-7-phenoxy-isoquinoline-3-carboxylic acid; MS-(+)-ion: M+1=590.0.
D) [(1-dimethylamino formyl radical-4-hydroxyl-7-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-acetate
Be similar to instance D-79d), synthetic by [(4-benzyloxy-1-dimethylamino formyl radical-7-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-jasmal; MS-(+)-ion: M+1=410.0.
Instance D-85
[(4-hydroxyl-1-methoxymethyl-7-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-acetate
A) 4-benzyloxy-1-methoxymethyl-7-phenoxy-isoquinoline-3-carboxylic acid benzyl ester
Be similar to instance D-78a), synthetic by 1-bromo-4-hydroxyl-7-phenoxy-isoquinoline-3-carboxylic acid (instance D-81a); MS-(+)-ion: M+1=506.2.
B) 4-benzyloxy-1-methoxymethyl-7-phenoxy-isoquinoline-3-carboxylic acid
Be similar to instance D-78b), synthetic by 4-benzyloxy-1-methoxymethyl-7-phenoxy-isoquinoline-3-carboxylic acid benzyl ester; MS-(-)-ion: M-1=414.1.
C) [(4-benzyloxy-1-methoxymethyl-7-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-jasmal
Be similar to instance D-78c), synthetic by 4-benzyloxy-1-methoxymethyl-7-phenoxy-isoquinoline-3-carboxylic acid; MS-(+)-ion: M+1=563.1.
D) [(4-hydroxyl-1-methoxymethyl-7-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-acetate
Be similar to instance D-78d), synthetic by [(4-benzyloxy-1-methoxymethyl-7-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-jasmal; MS-(+)-ion: M+1=383.0.
Instance D-86
[(4-hydroxyl-1-right-tolyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
A) 4-benzyloxy-1-bromo-isoquinoline-3-carboxylic acid butyl ester
Under agitation with 1-bromo-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (6.48g, 20mmol; Instance D-28a), bromotoluene (3.6ml, 30mmol), K 2CO 3(12.44g, 90mmol) and the mixture of acetone (300ml) refluxed 2.5 days.Follow evaporating solvent in a vacuum.Water (100ml) is added in the resistates and extracts this mixture with EtOAc (100ml).Via MgSO 4Dry organic phase is also evaporated the title compound that is little yellow solid with generation in a vacuum; MS-(+)-ion: M+1=414.1.
B) 4-benzyloxy-1-right-tolyl-isoquinoline-3-carboxylic acid butyl ester
With 4-benzyloxy-1-bromo-isoquinoline-3-carboxylic acid butyl ester (207mg, 0.5mmol) and Pd (PPh 3) 4(23mg 0.02mmol) is dissolved among the THF (3ml) and with this solution stirring 10min, adds right-tolyl boric acid (68mg, (0.5ml) solution of EtOH 0.5mmol) and Na then 2CO 3(106mg, water 1mmol) (0.5ml) solution.Gained mixture 4h under agitation refluxes.Subsequently, concentrate this mixture in a vacuum.Water (2ml) is added in the resistates and extracts this mixture with EtOAc (10ml).Via MgSO 4Dry organic phase is also evaporated to produce little yellow oil (225mg) in a vacuum.On silica gel, use hexane through flash column chromatography: EtOAc=94:6 comes purifying as elutriant, produces the title compound that is water white oil; MS-(+)-ion: M+1=426.2.
C) 4-hydroxyl-1-right-tolyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance D-78d) (with EtOAc as solvent), by 4-benzyloxy-1-right-tolyl-isoquinoline-3-carboxylic acid butyl ester is synthetic; MS-(+)-ion: M+1=336.2.
D) [(4-hydroxyl-1-right-tolyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
Be similar to instance D-1g), by 4-hydroxyl-1-right-tolyl-isoquinoline-3-carboxylic acid butyl ester is synthetic; MS-(+)-ion: M+1=337.1.
Instance D-87
{ [7-(4-fluoro-phenoxy)-4-hydroxyl-1-methyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate
A) 1-bromo-7-(4-fluoro-phenoxy)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance D-1e), by 7-(4-fluoro-phenoxy)-1,4-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester (instance D-96e) is synthetic; 1H NMR (CDCl 3): δ=11.89 (s, 1H), 8.36 (d, 1H), 7.44-7.57 (m, 2H), 7.08-7.25 (m, 4H), 4.47 (q, 2H), 1.85 (m, 2H), 1.50 (m, 2H), 0.99 (t, 3H).
B) 7-(4-fluoro-phenoxy)-4-hydroxyl-1-methyl-isoquinoline-3-carboxylic acid butyl ester
Under agitation reflux 1-bromo-7-(4-fluoro-phenoxy)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (434mg, 1mmol), Pd (PPh 3) 4(116mg, 0.1mmol), trimethylboroxin (140 μ l, 1mmol), K 2CO 3(414mg, 3mmol) with 1, the mixture 2h of 4-dioxane (8ml).Concentrate this mixture subsequently in a vacuum.(10ml) is added in the resistates with water.Through adding 6N HCl this mixture of acidified aqueous solution and then extracting with EtOAc (40ml).Via MgSO 4Dry organic phase and evaporation in a vacuum.On silica gel, use hexane: EtOAc=94 through flash column chromatography: 6 come the purifying resistates as elutriant, produce the solid title compound (229mg) that is white in color; MS-(+)-ion: M+1=370.1.
C) { [7-(4-fluoro-phenoxy)-4-hydroxyl-1-methyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate
Be similar to instance D-1g), synthetic by 7-(4-fluoro-phenoxy)-4-hydroxyl-1-methyl-isoquinoline-3-carboxylic acid butyl ester; MS-(+)-ion: M+1=371.1.
Instance D-88
{ [1-chloro-4-hydroxyl-7-(4-methoxyl group-phenoxy)-isoquinoline 99.9-3-carbonyl]-amino }-acetate
A) 4-(4-methoxyl group-phenoxy)-phthalonitrile
4-nitro-phthalonitrile (4.00g), 4-methoxyl group-phenol (3.46g) and the mixture heating up of salt of wormwood (6.39g) in acetone (64ml) to refluxing, are continued 2h.Reaction mixture is also filtered.Filtrate is concentrated and resistates is dissolved in the ETHYLE ACETATE (100ml).With NaOH (1N, 50ml), water and then clean this solution with salt solution.Via dried over mgso organic layer, filtration and concentrated to produce product (6.14g). 1H?NMR(200MHz,CDCl 3)δ6.70(d,J=7.8Hz,1H),7.21(m,2H),6.96(m,4H),3.84(s,3H)。
B) 4-(4-methoxyl group-phenoxy)-phthalic acid
Be similar to instance D-1a) prepare.MS-(-)-ion: M-1=286.9.
C) [5-(4-methoxyl group-phenoxy)-1,3-dioxy-1,3-dihydro-isoindole-2-yl]-methyl acetate
Be similar to instance D-37b) prepare. 1H?NMR(200MHz,CDC1 3)δ7.74(d,J=8.6Hz,1H),7.25(m,2H),6.98(m,4H),4.40(s,2H),3.83(s,3H),3.75(s,3H)。
D) 6-and 7-(4-methoxyl group-phenoxy)-1,4-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance D-21b) prepare.MS-(+)-ion: M+1=384.10.
E) 7-(4-methoxyl group-phenoxy)-1,4-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance D-21c) prepare.MS-(+)-ion: M+1=384.11.
F) 1-chloro-4-hydroxyl-7-(4-methoxyl group-phenoxy)-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance D-43d) prepare.MS-(+)-ion: M+1=402.0.
G) { [1-chloro-4-hydroxyl-7-(4-methoxyl group-phenoxy)-isoquinoline 99.9-3-carbonyl]-amino }-acetate
Be similar to instance D-1g) prepare.MS-(-)-ion: M-1=400.96.
Instance D-89
{ [4-hydroxyl-7-(4-methoxyl group-phenoxy)-isoquinoline 99.9-3-carbonyl]-amino }-acetate
A) { [4-hydroxyl-7-(4-methoxyl group-phenoxy)-isoquinoline 99.9-3-carbonyl]-amino }-acetate
Be similar to instance D-25, synthetic by { [1-chloro-4-hydroxyl-7-(4-methoxyl group-phenoxy)-isoquinoline 99.9-3-carbonyl]-amino }-acetate; MS-(-)-ion: M-1=367.0.
Instance D-90
{ [1-chloro-4-hydroxyl-6-(4-methoxyl group-phenoxy)-isoquinoline 99.9-3-carbonyl]-amino }-acetate
A) 6-(4-methoxyl group-phenoxy)-1,4-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester
By obtaining from instance D-88e) 6-and 7-(4-methoxyl group-phenoxy)-1, the mixture separation of 4-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester.MS-(+)-ion: M+1=384.1.
B) 1-chloro-4-hydroxyl-6-(4-methoxyl group-phenoxy)-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance D-43d) prepare.MS-(+)-ion: M+1=402.0.
C) { [1-chloro-4-hydroxyl-6-(4-methoxyl group-phenoxy)-isoquinoline 99.9-3-carbonyl]-amino }-acetate
Be similar to instance D-1g) prepare.MS-(+)-ion: M+1=403.0.
Instance D-91
{ [4-hydroxyl-6-(4-methoxyl group-phenoxy)-isoquinoline 99.9-3-carbonyl]-amino }-acetate
Be similar to instance D-2a), prepare by { [1-chloro-4-hydroxyl-6-(4-methoxyl group-phenoxy)-isoquinoline 99.9-3-carbonyl]-amino }-acetate.MS-(-)-ion: M-1=367.0.
The compound of following instance D-92-99 is to obtain through the method that is similar to described in the instance D88-D91.
Instance D-92
{ [1-chloro-4-hydroxyl-7-(4-trifluoromethyl-phenoxy)-isoquinoline 99.9-3-carbonyl]-amino }-acetate
A) 4-(4-trifluoromethyl-phenoxy)-phthalonitrile
1H?NMR(200MHz,CDC1 3)δ7.74(m,2H),7.47(d,J=8.6Hz,1H),7.25(m,3H),6.87(d,J=8.9Hz,1H)。
B) 4-(4-trifluoromethyl-phenoxy)-phthalic acid
1H?NMR(200MHz,DMSO-d 6)δ8.24(d,J=9.0Hz,1H),7.75(m,3H),7.19(m,3H)。
C) [1,3-dioxy-5-(4-trifluoromethyl-phenoxy)-1,3-dihydro-isoindole-2-yl)-methyl acetate
1H?NMR(200MHz,CDC1 3)δ7.86(d,J=8.5Hz,1H),7.67(d,J=8.2Hz,2H),7.40-7.13(m,4H),4.43(s,2H),3.769s,3H)。
D) 6-and 7-(4-trifluoromethyl-phenoxy)-1,4-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester
Two kinds of mixture of isomers.
E) 7-(4-trifluoromethyl-phenoxy)-1,4-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester
MS-(+)-ion: M+1=422.0.
F) 1-chloro-4-hydroxyl-7-(4-trifluoromethyl-phenoxy)-isoquinoline-3-carboxylic acid butyl ester
MS-(-)-ion: M-1=438.3.
G) { [1-chloro-4-hydroxyl-7-(4-trifluoromethyl-phenoxy)-isoquinoline 99.9-3-carbonyl]-amino }-acetate
MS-(-)-ion: M-1=439.0.
Instance D-93
{ [4-hydroxyl-7-(4-trifluoromethyl-phenoxy)-isoquinoline 99.9-3-carbonyl]-amino }-acetate
MS-(-)-ion: M-1=405.1.
Instance D-94
{ [1-chloro-4-hydroxyl-6-(4-trifluoromethyl-phenoxy)-isoquinoline 99.9-3-carbonyl]-amino }-acetate
A) 1,4-dihydroxyl-6-(4-trifluoromethyl-phenoxy)-isoquinoline-3-carboxylic acid butyl ester
MS-(+)-ion: M+1=422.0.
B) 1-chloro-4-hydroxyl-6-(4-trifluoromethyl-phenoxy)-isoquinoline-3-carboxylic acid butyl ester
1H?NMR(200MHz,CDC1 3)δ11.82(s,1H),8.30(d,J=9.0Hz,1H),7.81(d,J=2.3Hz,1H),7.67(d,J=8.6Hz,2H),7.54(dd,J=9.0,2.7Hz,1H),7.18(d,J=8.2Hz,2H),4.48(t,J=7.0Hz,2H),1.85(m,2H),1.46(m,2H),0.98(t,J=7.0Hz,3H)。
C) { [1-chloro-4-hydroxyl-6-(4-trifluoromethyl-phenoxy)-isoquinoline 99.9-3-carbonyl]-amino }-acetate
MS-(-)-ion: M-1=439.1.
Instance D-95
{ [4-hydroxyl-6-(4-trifluoromethyl-phenoxy)-isoquinoline 99.9-3-carbonyl]-amino }-acetate
MS-(-)-ion: M-1=405.0.
Instance D-96
{ [1-chloro-7-(4-fluoro-phenoxy)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate
A) 4-(4-fluoro-phenoxy)-phthalonitrile
1H?NMR(200MHz,CDC1 3)δ7.71(d,J=8.6Hz,1H),7.23-7.15(m,6H)。
B) 4-(4-fluoro-phenoxy)-phthalic acid
1H?NMR(200MHz,CDC1 3)δ7.74(d,J=8.9Hz,1H),7.33-7.15(m,6H)。
C) [5-(4-fluoro-phenoxy)-1,3-dioxy-1,3-dihydro-isoindole-2-yl]-methyl acetate
1H?NMR(200MHz,CDCl 3)δ7.80(d,J=7.4Hz,1H),7.28(m,2H),7.08(m,4H),4.41(s,2H),3.76(s,3H)。
D) 6-and 7-(4-fluoro-phenoxy)-1,4-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester
Two kinds of mixture of isomers.
E) 7-(4-fluoro-phenoxy)-1,4-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester
MS-(+)-ion: M+1=372.1.
F) 1-chloro-7-(4-fluoro-phenoxy)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
1H?NMR(200MHz,CDCl 3)δ11.90(s,1H),8.36(d,J=9.0Hz,1H),7.56(m,2H),7.10(m,4H),4.47(t,J=7.0Hz,2H),1.85(m,2H),1.46(m,2H),0.99(t,J=7.4Hz,3H)。
G) { [1-chloro-7-(4-fluoro-phenoxy)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate
MS-(-)-ion: M-1=389.0.
Instance D-97
{ [7-(4-fluoro-phenoxy)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate
MS-(-)-ion: M-1=355.1.
Instance D-98
{ [1-chloro-6-(4-fluoro-phenoxy)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate
A) 6-(4-fluoro-phenoxy)-1,4-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester
MS-(+)-ion: M+1=372.1.
B) 1-chloro-6-(4-fluoro-phenoxy)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
1H?NMR(200MHz,CDC1 3)δ11.77(s,1H),8.25(d,J=9.0Hz,1H),7.62(d,J=2.3Hz,1H),7.50(dd,J=9.0,2.3Hz,1H),7.10(m,4H),4.46(t,J=7.0Hz,2H),1.85(m,2H),1.45(m,2H),0.98(t,J=7.4Hz,3H)。
C) { [1-chloro-6-(4-fluoro-phenoxy)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate
MS-(-)-ion: M-1=389.1.
Instance D-99
{ [6-(4-fluoro-phenoxy)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate
MS-(-)-ion: M-1=355.1.
Instance D-100
{ [4-hydroxyl-7-(pyridin-4-yl sulfenyl)-isoquinoline 99.9-3-carbonyl]-amino }-acetate
A) 4-(pyridin-4-yl sulfenyl)-phthalonitrile
At N, the mixture heating up to 85 in N-dimethyl--methane amide (160ml) ℃ also stirs 3h with 4-nitro-phthalonitrile (17.28g), pyridine-4-mercaptan (10.68g) and salt of wormwood (25.17g).After the cooling, through the Celite pad filter reaction mixture and use rinsed.Concentrating filtrate also produces title compound 13.29g through silica gel chromatography (with the eluent ethyl acetate of the 15-30% in the methylene dichloride) purifying resistates second in a vacuum. 1H?NMR(200MHz,CDC1 3)δ8.59(d,J=6.2Hz,2H),7.68(m,3H),7.24(d,J=6.3Hz,2H)。
B) 4-(pyridin-4-yl sulfenyl)-phthalic acid
Be similar to instance D-1a) prepare.MS-(+)-ion: M+1=276.1.
C) [1,3-dioxy-5-(pyridin-4-yl sulfenyl)-1,3-dihydro-isoindole-2-yl)-butylacetate
Heat 20min and evaporate until bubble and stop effectively stirring down in oil bath (250 ℃) solid mixture with 4-(pyridin-4-yl sulfenyl)-phthalic acid (11.40g) and the positive butyl ester hydrochloride of glycocoll (6.95g).After the cooling, it is divided between ETHYLE ACETATE (300ml) and saturated sodium bicarbonate aqueous solution (150ml) dissolve.Separates two is also with ETHYLE ACETATE (300ml) aqueous layer extracted.With salt solution cleaning merging organic layer, via dried over mgso, filtration and concentrated to produce title compound 10.70g.MS-(+)-ion: M+1=371.2.
D) 6-and 7-(pyridin-4-yl sulfenyl)-1,4-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance D-21b) prepare.
E) 6-and 7-(pyridin-4-yl sulfenyl)-1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance D-43d) prepare.MS-(+)-ion: M+1=389.1.
F) 6-and 7-(pyridin-4-yl sulfenyl)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance D-1f) prepare.Through silica gel chromatography (the 50%-80% ETHYLE ACETATE in the methylene dichloride) purifying crude product to produce 7-(pyridin-4-yl sulfenyl)-1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester ((MS-(+)-ion: M+1=355.04) and 6-(pyridin-4-yl sulfenyl)-1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester ((MS-(+)-ion: M+1=355.13) of Compound D-100B) of Compound D-100A).
G) { [4-hydroxyl-7-(pyridin-4-yl sulfenyl)-isoquinoline 99.9-3-carbonyl]-amino }-acetate
Be similar to instance D-1g) prepare.MS-(+)-ion: M+1=356.1.
Instance D-101
{ [4-hydroxyl-6-(pyridin-4-yl sulfenyl)-isoquinoline 99.9-3-carbonyl]-amino }-acetate
Be similar to instance D-1g), by 6-(pyridin-4-yl sulfenyl)-1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-100B) prepare.MS-(+)-ion: M+1=356.1.
Instance D-102
[(7-benzenesulfinyl-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
A) 7-benzenesulfinyl-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
At room temperature with 4-hydroxyl-7-phenyl sulfenyl-isoquinoline-3-carboxylic acid butyl ester (300mg) and
Figure BDA00001645958401391
(Du Pont's speciality chemical (Dupont Specialty Chemicals); Willmington; DE, USA) (366mg) slurry mixture in (3/2) methanol (5ml) stirs 4h.Reaction mixture is divided between methylene dichloride and saturated sodium bicarbonate aqueous solution to be dissolved.Clean organic layer with saturated sodium bicarbonate aqueous solution and water.Via dried over mgso and filtration.With filtrate concentrate and through silica gel chromatography (0%-50% ETHYLE ACETATE in the methylene dichloride) purifying resistates to produce title compound 7-benzenesulfinyl-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-102A) (50mg) (MS-(+)-ion: M+1=370.1) with 7-benzenesulfonyl-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester ((90mg) (MS-(+)-ion: M+1=386.1) of Compound D-102B).
B) [(7-benzenesulfinyl-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
Be similar to instance D-1g), by 7-benzenesulfinyl-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-102A) prepare.MS-(+)-ion: M+1=371.1.
Instance D-103
[(7-benzenesulfonyl-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
Be similar to instance D-1g), by 7-benzenesulfonyl-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-102B) prepare.MS-(+)-ion: M+1=387.1.
Instance D-104
[(6-benzenesulfinyl-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
A) 6-benzenesulfinyl-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance B-18a), prepare by 4-hydroxyl-6-phenyl sulfenyl-isoquinoline-3-carboxylic acid butyl ester.Separate two kinds of compounds through chromatography: title compound 6-benzenesulfinyl-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester ((MS-(+)-ion: of Compound D-104A) M+1=370.1) with 6-benzenesulfonyl-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester ((MS-(+)-ion: M+1=386.1) of Compound D-104B).
B) [(6-benzenesulfinyl-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
Be similar to instance D-1g), by 6-benzenesulfinyl-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-104A) prepare.MS-(-)-ion: M-1=369.0.
Instance D-105
[(6-benzenesulfonyl-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
Be similar to instance D-1g), by 6-benzenesulfonyl-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-104B) prepare.MS-(-)-ion: M-1=385.1.
Instance D-106
[(6-amino-4-hydroxy-isoquinoline 99.9-3-carbonyl)-amino]-acetate
A) (5-nitro-1,3-dioxy-1,3-dihydro-isoindole-2-yl)-ETHYLE ACETATE
(57.8g) is added into 5-nitro-isoindole-1 with salt of wormwood, in 3-diketone (26.2g) and the solution mixture of METHYL BROMOACETATE (25.1g) in acetone (500ml).With gained mixture reflux (18h) whole night.After the cooling, filter reaction mixture is also used rinsed.Filtrate is concentrated and with resistates wet-milling in ether (200ml).Collect solid and wash with ether.Dried in vacuum is to produce title compound 231.9g. 1H?NMR(200MHz,CDC1 3)δ8.69(m,2H),8.07(d,J=8.2Hz,1H),4.48(s,2H),4.24(q,J=7.0Hz,2H),1.30(t,J=7.0Hz,3H)。
B) (5-amino-1,3-dioxy-1,3-dihydro-isoindole-2-yl)-ETHYLE ACETATE
10% palladium/C (50% is wet) solid (2.0g) is added in (5-nitro-1,3-dioxy-1,3-dihydro-isoindole-2-the yl)-solution mixture of ETHYLE ACETATE (10.0g) in Glacial acetic acid min. 99.5 (150ml).At H 2(storage pressure) following room temperature vigorous stirring is (18h) whole night.Leach catalyzer and use dichloromethane rinse through Celite pad.Concentrating filtrate is to produce title compound (7.0g). 1H?NMR(200MHz,CDCl 3)δ7.59(d,J=8.2Hz,1H),7.02(d,J=2.0Hz,1H),6.81(dd,J=8.2,2.0Hz,1H),4.38(br?S,2H),4.36(s,2H),4.20(q,J=7.0Hz,2H),1.27(t,J=7.0Hz,3H)。
C) [5-(diphenylmethylene-amino)-1,3-dioxy-1,3-dihydro-isoindole-2-yl]-ETHYLE ACETATE
Titanium tetrachloride slowly is added in (5-amino-1,3-dioxy-1,3-dihydro-isoindole-2-yl)-ETHYLE ACETATE (3.48g), UVNUL MS-40 (2.81g) and the mixture of DABCO (4.72g) in chlorobenzene (112mg).The mixture heating up of gained is extremely refluxed, continue 2.5h.After the cooling, through the Celite pad filter reaction mixture and use rinsed.Concentrating filtrate also passes through silica gel chromatography (the 25%-40% ETHYLE ACETATE in the hexane) purifying resistates to produce title compound (3.03g).MS-(+)-ion: M+1=413.3.
D) 6-and 7-(diphenylmethylene-amino)-1,4-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance D-21b) prepare.MS-(+)-ion: M+1=441.2.
E) 6-and 7-amino-1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance D-43d) prepare.Through silica gel chromatography (with 50% eluent ethyl acetate in the hexane) purifying crude product to produce title compound.MS-(+)-ion: M+1=295.1.
F) 6-and 7-amino-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester
10%Pd/C (50% wet) (110mg) is added in ETHYLE ACETATE (5ml) solution of 6-and 7-amino-1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (220mg) and also then adds ammonium formiate (471mg).The mixture heating up of gained is extremely refluxed, continue 0.5h.After the cooling, with ETHYLE ACETATE (50ml) diluted reaction mixture and filtration.Concentrating filtrate is to produce title compound (182mg).MS-(+)-ion: M+1=261.2.
G) 6-and 7-amino-4-(4-methoxyl group-benzenesulfonyl oxygen base)-isoquinoline-3-carboxylic acid butyl ester
At room temperature 6-and 7-amino-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (180mg), 4-methoxyl group-benzene sulfonyl chloride (145mg) and triethylamine (85mg) mixture in methylene dichloride (7ml) are stirred 18h.Water (20ml) is 4 with its dilution and use 0.1N HCl acidified aqueous solution to pH value.Separate two and also use the dichloromethane extraction water layer mutually.Clean the merging organic phase with salt solution, via dried over mgso, filtration and concentrated.Produce two kinds of products through silica gel chromatography (the 55%-80% ETHYLE ACETATE in the hexane) purifying crude product: 7-amino-4-(4-methoxyl group-benzenesulfonyl oxygen base)-isoquinoline-3-carboxylic acid butyl ester (Compound D-106A) (79mg) (MS-(+)-ion: M+1=431.1) with 6-amino-4-(4-methoxyl group-benzenesulfonyl oxygen base)-isoquinoline-3-carboxylic acid butyl ester ((70mg) (MS-(+)-ion: M+1=431.1) of Compound D-106B).
H) [(6-amino-4-hydroxy-isoquinoline 99.9-3-carbonyl)-amino]-acetate
Be similar to instance D-1g), by 6-amino-4-(4-methoxyl group-benzenesulfonyl oxygen base)-isoquinoline-3-carboxylic acid butyl ester (Compound D-106B) preparation.MS-(-)-ion: M-1=260.1.
Instance D-107
{ [4-hydroxyl-7-(4-methoxyl group-phenylsulfonamido)-isoquinoline 99.9-3-carbonyl]-amino }-acetate
A) 7-[(N, N-two-4-methoxyl group-benzenesulfonyl) amino]-4-(4-methoxyl group-benzenesulfonyl oxygen base)-isoquinoline-3-carboxylic acid butyl ester
(Compound D-106A) (75mg), 4-methoxyl group-benzene sulfonyl chloride (140mg) and the mixture heating up to 120 of triethylamine (76mg) in methylene dichloride (2ml) ℃ continue 10min with the 7-amino-4-in the sealed vessel (4-methoxyl group-benzenesulfonyl oxygen base)-isoquinoline-3-carboxylic acid butyl ester in microwave reactor.After the cooling, concentrated reaction mixture also passes through silica gel chromatography (with the 5%-10% eluent ethyl acetate in the methylene dichloride) purifying to produce title compound (68mg).MS-(+)-ion: M+1=770.99.
B) { [4-hydroxyl-7-(4-methoxyl group-phenylsulfonamido)-isoquinoline 99.9-3-carbonyl]-amino }-acetate
In microwave reactor with mixture heating up in 0.5N sodium methylate/methyl alcohol (2.7ml) of the above-mentioned ester (68mg) in the sealed vessel and glycocoll (86mg) (150 ℃, 17min).After the cooling, concentrated reaction mixture.Resistates is dissolved in the water (10ml) and extracts with ETHYLE ACETATE (15ml).Through the 2N HCl aqueous solution water layer is acidified to pH=4 also with ETHYLE ACETATE (2 * 50ml) extractions.Clean the merging organic layer with salt solution, via dried over mgso, filtration and concentrated.With methyl alcohol and (1/1) ethyl acetate/hexane wet-milling crude product, produce title compound 14mg.MS-(-)-ion: M-1=430.
Instance D-108
{ [4-hydroxyl 7-(3-phenyl-urea groups)-isoquinoline 99.9-3-carbonyl]-amino }-acetate
A) 6-and 7-(3-phenyl-urea groups)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
(18h) stirs 6-and 7-amino-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (160mg) and the mixture of phenylcarbimide (73mg) in methylene dichloride (4ml) and concentrates at room temperature whole night.With (1/1) ethyl acetate/dichloromethane (8ml) wet-milling resistates.Through filtering the collection insoluble solids and washing with methylene dichloride (5ml).Dry to produce 7-(3-phenyl-urea groups)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester ((82mg) (MS-(+)-ion: M+1=380.18) of Compound D-108A).With filtrate concentrate and through silica gel chromatography purifying resistates and then from methyl alcohol recrystallize to produce 6-(3-phenyl-urea groups)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester ((82mg) (MS-(+)-ion: M+1=380.15) of Compound D-108B).
B) { [4-hydroxyl 7-(3-phenyl-urea groups)-isoquinoline 99.9-3-carbonyl]-amino }-acetate
Be similar to instance D-1g), by 7-(3-phenyl-urea groups)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-108A) preparation.MS-(-)-ion: M-1=379.07.
Instance D-109
{ [4-hydroxyl-6-(3-phenyl-urea groups)-isoquinoline 99.9-3-carbonyl]-amino }-acetate
A) { [4-hydroxyl-6-(3-phenyl-urea groups)-isoquinoline 99.9-3-carbonyl]-amino }-acetate
Be similar to instance D-1g), by 7-(3-phenyl-urea groups)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-108B) preparation.MS-(-)-ion: M-1=379.08.
Instance D-110
[(4-hydroxyl-1-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
Be prepared as follows title compound: the 1.2ml benzenethiol is added into 250mg [(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate (USP 6; 093; 730, be disclosed as N-((1-chloro-4-hydroxyl isoquinoline 99.9-3-yl) carbonyl) glycocoll) be dissolved in the solution in the 1ml1-N-methyl-2-2-pyrrolidone N-.In ST, heat 16h with under in 130 to 150 ℃ of this solution.Solution is concentrated under vacuum.Crystallization gained resistates is to obtain the pale brown look solid of 91mg from methyl alcohol; MS (-) m/z353.07 (M-1).
Instance D-111
{ [1-(4-chloro-phenyl sulfenyl)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate
Under the condition that is similar to instance D-110, prepare title compound by [(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate (USP 6,093,730) and 4-chlorobenzene mercaptan; MS (+) m/z 389.06 (M+1).
Instance D-112
[(4-hydroxyl-1-right-tolyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
Under the condition that is similar to instance D-110, prepare title compound by [(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate (USP 6,093,730) and 4-methylbenzene mercaptan; MS (-) m/z 367.09 (M-1).
Instance D-113
[(4-hydroxyl-1-(pyridine-2-base sulfenyl)-isoquinoline 99.9-3-carbonyl)-amino]-acetate
Under the condition that is similar to instance D-110, prepare title compound by [(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate (USP 6,093,730) and 2-mercaptopyridine.On silica gel, use 3-15% methyl alcohol and 0.5% acetate gradient elution product in the methylene dichloride to come the purifying final product through column chromatography; MS (-) m/z 354.10 (M-1).
Instance D-114
{ [4-hydroxyl-1-(3-methoxyl group-phenyl sulfenyl)-isoquinoline 99.9-3-carbonyl]-amino }-acetate
Under the condition that is similar to instance D-110, prepare title compound by [(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate (USP 6,093,730) and 3-anisole mercaptan.Use hexane that final product is precipitated from the solution of ETHYLE ACETATE; MS (-) m/z 385.12 (M-1).
Instance D-115
{ [4-hydroxyl-1-(2-methoxyl group-phenyl sulfenyl)-isoquinoline 99.9-3-carbonyl]-amino }-acetate
Under the condition that is similar to instance D-110, prepare title compound by [(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate (USP 6,093,730) and 2-anisole mercaptan.Make final product crystallization from methylene dichloride; MS (-) m/z 383.08 (M-1).
Instance D-116
{ [4-hydroxyl-1-(naphthalene-2-base sulfenyl)-isoquinoline 99.9-3-carbonyl]-amino }-acetate
Under the condition that is similar to instance D-110, prepare title compound by [(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate (USP 6,093,730) and 2-naphthyl mercaptan.Through also coming the purifying final product 2 times 2 times with the methylene dichloride wet-milling with methyl alcohol wet-milling crude product; MS (+) m/z 405.08 (M+1).
Instance D-117
[(1-benzenesulfinyl-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
Be prepared as follows title compound: 50mg [(4-hydroxyl-1-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate (instance D-110) is dissolved in 0.3ml1-N-methyl-2-2-pyrrolidone N-and the 0.7ml methylene dichloride.Solution is cooled to 0 ℃ and add 26mg 75%3-chlorine peroxybenzoic acid.At room temperature stirred this solution 2 hours, and then under high vacuum, concentrated.With ETHYLE ACETATE wet-milling gained resistates, obtain the 32mg solid product that is white in color; MS (-) m/z 369.08 (M-1).
Instance D-118
[(1-benzenesulfonyl-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
Be prepared as follows title compound: 50mg [(4-hydroxyl-1-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate (instance D-110) is dissolved in 0.1ml1-N-methyl-2-2-pyrrolidone N-and the 0.7ml methylene dichloride.72mg 75%3-chlorine peroxybenzoic acid is added so far in the solution.At room temperature with this solution stirring 6 hours.Mixture is divided between ETHYLE ACETATE and water to be dissolved.Via organic part of anhydrous magnesium sulfate drying, and be concentrated into resistates.With ETHYLE ACETATE wet-milling gained resistates, obtain the 28mg solid product that is white in color; MS (-) m/z 385.09 (M-1).
Instance D-119
{ [4-hydroxyl-7-(pyridine-2-base sulfenyl)-isoquinoline 99.9-3-carbonyl]-amino }-acetate
A) 4-(pyridine-2-base sulfenyl)-phthalonitrile
With 10g 2-mercaptopyridine, 14.2g 4-nitrophthalonitrile and 22.6g salt of wormwood be suspended in the 250ml acetone and under reflux temperature the heating 4 hours.Filter this solution through Celite pad and water conservancy diversion glass filter and remove residual solid.On silica gel, come purifying with solution concentration to thick resistates and through column chromatography with the 0-10% ETHYLE ACETATE gradient elution product in the methylene dichloride.Reclaim the 6.4g product; 1H NMR (200Mz, CDC1 3) δ=8.49-8.53 (m, 1H), 7.84-7.83 (dd, 1H), 7.76-7.71 (m, 2H), 7.68-7.64 (dd, 1H), 7.40-7.36 (dt, 1H), 7.27-7.20 (m, 1H).
B) { [4-hydroxyl-7-(pyridine-2-base sulfenyl)-isoquinoline 99.9-3-carbonyl]-amino }-acetate
Be similar to instance D-1, prepare title compound by 4-(pyridine-2-base sulfenyl)-phthalonitrile; MS (+): m/z356.01 (M+1).
Instance D-120
{ [4-hydroxyl-6-(pyridine-2-base sulfenyl)-isoquinoline 99.9-3-carbonyl]-amino }-acetate
Be similar to instance D-119, prepare title compound by 4-(pyridine-2-base sulfenyl)-phthalonitrile; MS (+): m/z356.02 (M+1).
Instance D-121
[(1-chloro-4-hydroxyl-6,7-two phenoxys-isoquinoline 99.9-3-carbonyl)-amino]-acetate
A) 4,5-two phenoxy phthalonitriles
With 5.0g 4,5-dichloro phthalonitrile is dissolved in and adds 14.3g phenol among the 50ml DMSO and solution is heated to 90 ℃.Added 6.9g salt of wormwood in per 5 minutes until adding 55.2g altogether.Stir this compound 30min at 90 ℃, then cooling and injection 500ml frozen water.Collect the gained solid sediment and from methyl alcohol crystallization 3.6g is provided product; 1H NMR (200Mz, CDC1 3) δ=7.49-7.38 (m, 4H), 7.32-7.25 (m, 2H), 7.15 (s, 2H) 57.10-7.02 (m, 4H).
B) [(1-chloro-4-hydroxyl-6,7-two phenoxys-isoquinoline 99.9-3-carbonyl)-amino]-acetate
Be similar to instance D-7a-d and instance D-9a-b, by 4,5-two phenoxy phthalonitrile synthesising title compounds; MS (+): m/z 465.05 (M+1).
Instance D-122
[(4-hydroxyl-6,7-two phenoxys-isoquinoline 99.9-3-carbonyl)-amino]-acetate
Be similar to instance D-7, by 4,5-two phenoxy phthalonitriles (instance D-121a) synthesising title compound; MS (+): m/z 431.07 (M+1).
Instance D-123
({ 4-hydroxyl-7-[4-(toluene-4-sulfonamido)-phenoxy]-isoquinoline 99.9-3-carbonyl }-amino)-acetate
A) 1-chloro-4-hydroxyl-6-(4-nitro-phenoxy)-isoquinoline-3-carboxylic acid butyl ester
200mg 1-chloro-4-hydroxyl-6-phenoxy-isoquinoline-3-carboxylic acid butyl ester (instance D-10a) is dissolved in the 3ml vitriol oil.Reaction mixture is cooled to-20 ℃ and 60mg saltpetre slowly is added in the stirred solution.Reaction is remained between-10 to-20 ℃, stir 15min simultaneously, and be injected in the frozen water.With ETHYLE ACETATE water mixture is extracted 2 times.Clean organic part with saturated bicarbonate and salt brine solution successively, via anhydrous magnesium sulfate drying and be evaporated to resistates.Then use methyl alcohol wet-milling gained solid with the ETHYLE ACETATE wet-milling, produce the 103mg white solid; MS (+): m/z417.07 (M+1).
B) 6-(4-amino-phenoxy)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
100mg 1-chloro-4-hydroxyl-6-(4-nitro-phenoxy)-isoquinoline-3-carboxylic acid butyl ester is added in 3mlTHF and the 3ml methyl alcohol.20mg sodium acetate and 25mg 10% palladium on carbon are added so far in the mixture, and stirring reaction is placed under the nitrogen atmosphere (ball) whole night.Filter gained solution and be concentrated into resistates through Celite pad.On silica gel, come the thick material of purifying through column chromatography, produce the 59mg product with the 0-20% ETHYLE ACETATE gradient elution product in the methylene dichloride; MS (-): m/z 351.27 (M-1).
C) 4-hydroxyl-7-[4-(toluene-4-sulfonamido)-phenoxy]-isoquinoline-3-carboxylic acid butyl ester
With 58mg 6-(4-amino-phenoxy)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester, 15.8mg pyridine and 34mg p-toluenesulfonyl chloride are dissolved in the 0.3ml anhydrous methylene chloride.Stirred this mixture 16 hours, and then between 0.25N HCl and ETHYLE ACETATE, divide molten.Water, saturated bicarbonate and salt brine solution clean organic part successively, then via anhydrous sodium sulfate drying, and are concentrated into the thick solid of 84mg.Produce the 42mg white solid with this thick material of ETHYLE ACETATE wet-milling; 1H NMR (200Mz, CDC1 3) δ=11.7 (s, lH), 8.72 (d, 1H), 7.93-7.88 (d, 1H), 7.69-7.65 (d; 2H), and 7.56-7.54 (m, 2H), 7.44-7.39 (dd, 1H), 7.27-7.13 (m, 5H); 7.00-6.96 (d, 2H), 4.46 (t, 2H), 2.4 (s, 3H); 1.87-1.82 (quintet, 2H), 1.48-1.40 (quint, 2H), 1.00-0.95 (t, 3H).
D) ({ 4-hydroxyl-7-[4-(toluene-4-sulfonamido)-phenoxy]-isoquinoline 99.9-3-carbonyl }-amino)-acetate
42mg 4-hydroxyl-7-[4-(toluene-4-sulfonamido)-phenoxy]-isoquinoline-3-carboxylic acid butyl ester and 70mg glycocoll are added in the methanol solution of 1.85ml 0.5M sodium methylate.The gained mixture is heated 24h at reflux temperature, and then be cooled to room temperature.Reactant is injected the 0.2N HCl aqueous solution and then with ethyl acetate extraction 3 times.Via organic part of anhydrous sodium sulfate drying, and be concentrated into the 41mg white solid; MS (+): m/z 508.10 (M+1).
Instance D-124
{ [4-hydroxyl-7-(4-nitro-phenoxy)-isoquinoline 99.9-3-carbonyl]-amino }-acetate
A) 4-hydroxyl-7-(4-nitro-phenoxy)-isoquinoline-3-carboxylic acid butyl ester
2.0g 4-hydroxyl-7-phenoxy-isoquinoline-3-carboxylic acid butyl ester (instance D-7f) is dissolved among the 15ml TFA.The 0.375ml nitrosonitric acid is slowly added so far in the solution, and at room temperature stirred the gained mixture 7 hours.Concentrated reaction mixture under vacuum, and on silica gel, come purifying gained resistates with the 0-20% eluent ethyl acetate in the methylene dichloride through column chromatography.The crude product that is obtained with the methyl alcohol wet-milling produces the 1.0g white solid; MS (+): m/z 383.01 (M+1).
B) { [4-hydroxyl-7-(4-nitro-phenoxy)-isoquinoline 99.9-3-carbonyl]-amino }-acetate
Be similar to instance D-1g), by 4-hydroxyl-7-(4-nitro-phenoxy)-isoquinoline-3-carboxylic acid butyl ester synthesising title compound; MS (-): m/z 382.06 (M-1).
Instance D-125
[(4-sulfydryl-7-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-acetate
A) 4-dimethyl-thiocarbamyl oxygen base-7-phenoxy-isoquinoline-3-carboxylic acid butyl ester
For chloroformamide and 1.5g 1,4-diaza-bicyclo [2.2.2] octane is added into 1.5g 4-hydroxyl-7-phenoxy-isoquinoline-3-carboxylic acid butyl ester (instance D-7f) and is dissolved in the solution of 6.3ml dry DMF with the 578mg dimethyl sulphide.At room temperature stir this mixture whole night.Mixture is injected 30ml1N HCl and divides 3 extractions with 30ml ETHYLE ACETATE.Water and salt solution clean organic part, via anhydrous sodium sulfate drying and concentrated to produce the 1.9g product; MS (+) m/z 425.27 (M+1).
B) 4-dimethylamino formyl radical sulfenyl-7-phenoxy-isoquinoline-3-carboxylic acid butyl ester
The solution that 1.9g 4-dimethyl-thiocarbamyl oxygen base-7-phenoxy-isoquinoline-3-carboxylic acid butyl ester is dissolved in the 22ml phenyl ether is heated to 190 ℃, continues 2 hours.Under vacuum, concentrate this solution to produce thick resistates, it comes purifying with this product of 30-80% ETHYLE ACETATE gradient elution in the hexane through column chromatography on silica gel, produce 1.73g; MS (+) m/z 425.07 (M+1).
C) 4-sulfydryl-7-phenoxy-isoquinoline-3-carboxylic acid methyl esters
460mg 4-dimethylamino formyl radical sulfenyl-7-phenoxy-isoquinoline-3-carboxylic acid butyl ester is added in the methanol solution of 6.5ml 0.5N sodium methylate.Gained solution is heated to 50-60 ℃, continues 8 hours, be cooled to room temperature also with 10ml water and 7.0ml1N HCl dilution.Filter the yellow mercury oxide that this solution is collected gained through (medium) porous Bu Shi filter funnel, produce the 307mg product; MS (+) m/z 312.08 (M+1).
D) [(4-sulfydryl-7-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-acetate
75mg 4-sulfydryl-7-phenoxy-isoquinoline-3-carboxylic acid methyl esters and 181mg glycocoll are added in the methanol solution of 4.3ml 0.5M sodium methylate.(City State) with this mixture heating up to 150 ℃, continues 10min to use CEM Discover microwave reactor.Cooling gained solution also produces yellow mercury oxide with the acidifying of 1N HCl solution.Filter this solution through (medium) porous Bu Shi filter funnel and come the collecting precipitation thing, and produce the 68mg product with the methyl alcohol wet-milling; MS (-): m/z 353.02 (M-1).
Instance D-126
[(4-sulfydryl-7-trifluoromethyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
A) 4-hydroxyl-7-trifluoromethyl-isoquinoline-3-carboxylic acid butyl ester
Under the condition that is similar to instance D-7a-f, prepare title compound by 4-trifluoromethyl phthalic acid; MS (+) m/z 314.1 (M+1).
B) [(4-sulfydryl-7-trifluoromethyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
Under the condition that is similar to instance D-125, prepare title compound by 4-hydroxyl-7-trifluoromethyl-isoquinoline-3-carboxylic acid butyl ester; MS (-) m/z 328.33 (M-1).
Instance D-127
{ [7-(4-phenylsulfonamido-phenoxy)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate
Be similar to instance D-123b-d, in step c, replace p-toluenesulfonyl chloride, by 4-hydroxyl-7-(4-nitro-phenoxy)-isoquinoline-3-carboxylic acid butyl ester (instance D-124a) synthesising title compound with benzene sulfonyl chloride; MS (+): m/z 494.09 (M+1).
Instance D-128
{ [4-hydroxyl-7-(4-methanesulfonamido-phenoxy)-isoquinoline 99.9-3-carbonyl]-amino }-acetate
Be similar to instance D-123b-d, in step c, replace p-toluenesulfonyl chloride, by 4-hydroxyl-7-(4-nitro-phenoxy)-isoquinoline-3-carboxylic acid butyl ester (instance D-124a) synthesising title compound with benzene sulfonyl chloride; MS (-): m/z 430.03 (M-1).
Instance D-129
{ [7-(4-chloro-phenoxy)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate
A) 4-(4-chloro-phenoxy)-phthalonitrile
Be similar to instance D-88a) prepare. 1H?NMR(200MHz,DMSO)δ8.09(d,J=9Hz,1H),7.83(d,J=2.6,1H),7.53(d,J=8.6Hz,2H),7.42(dd,J=2.8,8.6Hz,1H),7.24(d,J=8.6,2H)。
B) 4-(4-chloro-phenoxy)-phthalic acid
Be similar to instance D-1a) prepare.MS-(-)-ion: M-1=291.0.
C) [5-(4-chloro-phenoxy)-1,3-dioxy-1,3-dihydro-isoindole-2-yl]-butylacetate
Be similar to instance D-100c) prepare. 1H?NMR(200MHz,DMSO)δ7.48(d,J=8.6Hz,1H),7.59(d,J=9.0Hz,2H),7.46(m,2H),7.29(d,J=9.0Hz,2H),4.46(s,2H),4.16(t,J=6.2Hz,2H),1.61(m,2H),1.38(m,2H),0.92(t,J=7.0Hz,3H)。
D) 6-and 7-(4-chloro-phenoxy)-1,4-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance D-1d) prepare.Two kinds of mixture of isomers.MS-(-)-ion: M-1=386.1.
E) 1-chloro-6-and 7-(4-chloro-phenoxy)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance D-43d) prepare.Two kinds of mixture of isomers.MS-(-)-ion: M-1=404.2.
F) 6-and 7-(4-chloro-phenoxy)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance D-1f) prepare.Separate two kinds of isomer and produce 7-(4-chloro-phenoxy)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-l29A): MS-(-)-ion: M-1=370.3 and 6-(4-chloro-phenoxy)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-l29B): MS-(-)-ion: M-1=370.3.
G) { [7-(4-chloro-phenoxy)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate
Be similar to instance D-37e), by 7-(4-chloro-phenoxy)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-129A) begin to prepare.MS-(-)-ion: M-1=371.0.
Instance D-130
{ [6-(4-chloro-phenoxy)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate
A) { [6-(4-chloro-phenoxy)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate
Be similar to instance D-37e), by 6-(4-chloro-phenoxy)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-129B) begin to prepare.MS-(-)-ion: M-1=371.1.
Instance D-131
{ [6-(3-fluoro-5-methoxyl group-phenoxy)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate
A) 4-(3,4-two fluoro-phenoxys)-phthalonitrile
Be similar to instance D-88a) prepare. 1H?NMR(200MHz,DMSO)δ8.14(d,J=9Hz,1H) 57.95(d,J=2.6,1H),7.56(dd,J=2.6,8.6Hz,1H),7.19(dt,J=2.4,9.2Hz,1H),7.04(m,2H)。
B) 4-(3-fluoro-5-methoxyl group-phenoxy)-phthalic acid
Be similar to instance D-1a) prepare.In hydrolysis, one fluorine-based is replaced by methoxyl group.MS-(-)-ion: M-1=305.0.
C) [5-(3-fluoro-5-methoxyl group-phenoxy)-1,3-dioxy-1,3-dihydro-isoindole-2-yl]-butylacetate
Be similar to instance D-100c) prepare. 1H?NMR(200MHz,DMSO)δ7.93(d,J=8.6Hz,1H),7.43(m,2H),6.79-6.63(m,3H),4.41(s,2H),4.10(t,J=6.2,2H),1.54(m,2H),1.30(m,2H),0.86(t,J=7.0,3H)。
D) 6-and 7-(3-fluoro-5-methoxyl group-phenoxy)-1,4-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance D-1d) prepare.Two kinds of mixture of isomers.MS-(-)-ion: M-1=400.1.
E) 1-chloro-6-and 7-(3-fluoro-5-methoxyl group-phenoxy)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance D-43d) prepare.Two kinds of mixture of isomers.MS-(-)-ion: M-1=418.3.
F) 6-and 7-(3-fluoro-5-methoxyl group-phenoxy)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
(50% is wet, 70mg) is added in ETHYLE ACETATE (3ml) solution of l-chloro-6-and 7-(3-fluoro-5-methoxyl group-phenoxy)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (176mg) also then to add ammonium formiate (264mg) with 10%Pd/C.The mixture heating up of gained is extremely refluxed, continue 0.5h.After the cooling, filter with the ETHYLE ACETATE diluted reaction mixture and through Celite pad.Concentrating filtrate and through chromatography separate with produce 64mg 7-(3-fluoro-5-methoxyl group-phenoxy)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-131A) and 74mg 6-(3-fluoro-5-methoxyl group-phenoxy)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-131B): 1H NMR (200MHz, CD 3OD) δ 8.73 (s, 1H) 58.15 (d, J=9.0Hz, 1H), 7.71 (s, 1H), 7.59 (m, 1H), 6.65-6.47 (m, 3H), 4.49 (t, J=6.6Hz, 2H), 3.81 (s, 3H), 1.87 (m, 2H), 1.56 (m, 2H), 1.03 (t, J=7.4,3H).
G) { [6-(3-fluoro-5-methoxyl group-phenoxy)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate
Be similar to instance D-37e), by 6-(3-fluoro-5-methoxyl group-phenoxy)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-131B) begin to prepare.MS-(-)-ion: M-1=385.1.
Instance D-132
{ [7-(3-fluoro-5-methoxyl group-phenoxy)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate
Be similar to instance D-37e), by 7-(3-fluoro-5-methoxyl group-phenoxy)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-131A) begin to prepare.MS-(-)-ion: M-1=385.1.
Instance D-133
{ [7-(3,4-two fluoro-phenoxys)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate
A) 5-(3,4-two fluoro-phenoxys)-isoindole-1, the 3-diketone
With 3,4-difluorophenol (650mg) and benzene azeotropic and be dissolved in the methanol solution of sodium methylate (0.5M, 10ml).Then decompression removes methyl alcohol under nitrogen.Then dry DMF (10ml) solution with 4-nitro phthalic imidine (769mg) is added in the mixture before.The mixture of gained is at refluxed under nitrogen 23h.With reaction cooled and add 80ml water.Filter the throw out of gained, water cleans (4 times) and dry title compound with generation 685mg.MS-(-)-ion: M-1=274.3.
B) [5-(3,4-two fluoro-phenoxys)-1,3-dioxy-1,3-dihydro-isoindole-2-yl]-methyl acetate
With 5-(3,4-two fluoro-phenoxys)-isoindole-1,3-diketone (680mg), salt of wormwood (1g), propione (20ml) and methyl bromoacetate (295 μ l) are added into pressure tube.With the mixture heating up to 105 of gained ℃, continue 17h.With 20ml water diluting reaction thing and with ethyl acetate extraction (2 times).Dry organic layer also concentrates.Through silica gel chromatography, use 4:1 hexane/ethyl acetate and 3:1 hexane/ethyl acetate purified mixture to produce the 657mg title compound: 1H NMR (200MHz, DMSO) δ 7.95 (d, J=9.0Hz, 1H), 7.64-7.41 (m, 4H), 7.15-7.08 (m, 1H), 4.44 (s, 2H), 3.70 (s, 3H).
C) 6-and 7-(3,4-two fluoro-phenoxys)-1,4-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance D-1d) prepare.Two kinds of mixture of isomers.MS-(-)-ion: M-1=388.1.
D) 1-chloro-6-and 7-(3,4-two fluoro-phenoxys)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance D-43d) prepare.Two kinds of mixture of isomers directly continue on for next step.
E) 6-and 7-(3,4-two fluoro-phenoxys)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance D-131f) prepare.Separate two kinds of isomer and produce 7-(3,4-two fluoro-phenoxys)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-133A) and 6-(3,4-two fluoro-phenoxys)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (compound 133B).
F) { [7-(3,4-two fluoro-phenoxys)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate
Be similar to instance D-37e), by 7-(3,4-two fluoro-phenoxys)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-133A) begin to prepare.MS-(-)-ion: M-1=373.2.
Instance D-134
{ [6-(3,4-two fluoro-phenoxys)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate
A) { [6-(3,4-two fluoro-phenoxys)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate
Be similar to instance D-37e), by 6-(3,4-two fluoro-phenoxys)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-133B) begin to prepare.MS-(-)-ion: M-1=373.2.
Instance D-135
{ [4-hydroxyl-7-(4-trifluoromethoxy-phenoxy)-isoquinoline 99.9-3-carbonyl]-amino }-acetate
A) 5-(4-trifluoromethoxy-phenoxy)-isoindole-1, the 3-diketone
Be similar to instance D-133a) prepare.MS-(-)-ion: M-1=322.3.
B) [1,3-dioxy-5-(4-trifluoromethoxy-phenoxy)-1,3-dihydro-isoindole-2-yl)-methyl acetate
Be similar to instance D-133b), refluxing prepares whole night. 1H?NMR(200MHz,CDC1 3)δ7.83(d,J=8.6,1H),7.34-7.24(m,4H),7.09(d,J=8.6,2H),4.42(s,2H),3.76(s,3H)。
C) 1,4-dihydroxyl-6-and 7-(3-trifluoromethoxy-phenoxy)-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance D-1d) prepare.Two kinds of mixture of isomers.MS-(-)-ion: M-1=436.2.
D) 1-chloro-4-hydroxyl-6-and 7-(3-trifluoromethoxy-phenoxy)-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance D-43d), use microwave reactor with toluene as solvent and use 1.5 equivalent POCl 3Prepare.Two kinds of mixture of isomers are directly continued on for next step.
E) 4-hydroxyl-6-and 7-(3-trifluoromethoxy-phenoxy)-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance D-131f) prepare.Separate two kinds of isomer and produce 4-hydroxyl-7-(3-trifluoromethoxy-phenoxy)-isoquinoline-3-carboxylic acid butyl ester (Compound D-135A): MS-(+)-ion: M+1=422.2 and 4-hydroxyl-6-(3-trifluoromethoxy-phenoxy)-isoquinoline-3-carboxylic acid butyl ester (Compound D-135B): MS-(-)-ion: M-1=420.6.
F) { [4-hydroxyl-7-(4-trifluoromethoxy-phenoxy)-isoquinoline 99.9-3-carbonyl]-amino }-acetate
Be similar to instance D-37e), by 4-hydroxyl-7-(3-trifluoromethoxy-phenoxy)-isoquinoline-3-carboxylic acid butyl ester (Compound D-135A) begin to prepare.MS-(-)-ion: M-1=421.2.
Instance D-136
{ [4-hydroxyl-6-(4-trifluoromethoxy-phenoxy)-isoquinoline 99.9-3-carbonyl]-amino }-acetate
Be similar to instance D-37e), by 4-hydroxyl-6-(3-trifluoromethoxy-phenoxy)-isoquinoline-3-carboxylic acid butyl ester (Compound D-135B) begin to prepare.MS-(-)-ion: M-1=421.1.
Instance D-137
{ [7-(3,5-two fluoro-phenoxys)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate
A) [5-(3,5-two fluoro-phenoxys)-1,3-dioxy-1,3-dihydro-isoindole-2-yl]-ETHYLE ACETATE
With (5-nitro-1,3-dioxy-1,3-dihydro-isoindole-2-yl)-ETHYLE ACETATE (2g), 3,5-difluorophenol (1.12g), salt of wormwood (1.39g) and N,N-DIMETHYLACETAMIDE (27ml) are added in the 80ml microwave reaction container.Make the gained mixture in microwave, react 10min in 100 ℃.Add water (280ml) and filter the gained throw out, clean and drying with water.Be further purified generation 0.94g title compound through silica gel chromatography. 1H?NMR(200MHz,CDC1 3)δ7.86(d,J=8.2Hz,1H),7.41-7.31(m,2H),6.67-6.57(m,3H),4.41(s,2H),4.22(q,J=7.1Hz,2H),1.29(t,J=7.0Hz,3H)。
B) 6-and 7-(3,5-two fluoro-phenoxys)-1,4-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance D-1d) prepare title product.Produce two kinds of mixture of isomers.MS-(+)-ion: M+1=390.1.
C) 1-chloro-6-and 7-(3,5-two fluoro-phenoxys)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance D-43d) prepare, just be reflected in the microwave reactor in 135 ℃ and carry out 10min, use toluene as solvent and 1.5 normal POCl 3Produce two kinds of mixture of isomers.MS-(-)-ion: M-1=406.2.
D) 6-and 7-(3,5-two fluoro-phenoxys)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance D-131f) prepare.Separate two kinds of isomer and produce 7-(3; 5-two fluoro-phenoxys)-and 4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-137A): MS-(-)-ion: M-1=372.2 and 6-(3,5-two fluoro-phenoxys)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-137B): MS-(+)-ion: M+1=374.1.
E) { [7-(3,5-two fluoro-phenoxys)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate
Be similar to instance D-37e), by 7-(3,5-two fluoro-phenoxys)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-137A) begin to prepare.MS-(-)-ion: M-1=373.1.
Instance D-138
{ [6-(3,5-two fluoro-phenoxys)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate
A) { [6-(3,5-two fluoro-phenoxys)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate
Be similar to instance D-37e), by 6-(3,5-two fluoro-phenoxys)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-137B) begin to prepare.MS-(-)-ion: M-1=373.1.
Instance D-139
({ 7-[4-(4-fluoro-phenoxy)-phenoxy]-4-hydroxyl-isoquinoline 99.9-3-carbonyl }-amino)-acetate
A) { 5-[4-(4-fluoro-phenoxy)-phenoxy]-1,3-dioxy-1,3-dihydro-isoindole-2-yl }-ETHYLE ACETATE
Be similar to instance D-137a), prepare through making (5-nitro-1,3-dioxy-1,3-dihydro-isoindole-2-yl)-ETHYLE ACETATE and 4-(4-fluoro-phenoxy)-phenol reactant. 1H?NMR(200MHz,CDC1 3)δ7.80(d,J=8.0Hz,1H),7.31(m,2H),7.06-7.01(m,8H),4.39(s,2H),4.21(q,J-7.2,2H),1.30(t,J=7.3,3H)。
B) 6-and 7-[4-(4-fluoro-phenoxy)-phenoxy]-1,4-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance D-1d) prepare.Produce two kinds of mixture of isomers.MS-(-)-ion: M-1=462.1.
C) 1-chloro-6-and 7-[4-(4-fluoro-phenoxy)-phenoxy]-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance D-137c) prepare.Produce two kinds of mixture of isomers.MS-(+)-ion: M+1=482.1.
D) 6-and 7-[4-(4-fluoro-phenoxy)-phenoxy]-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance D-131f) prepare.Separate two kinds of isomer and produce 7-[4-(4-fluoro-phenoxy)-phenoxy]-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-139A): MS-(+)-ion: M+1=448.1 and 6-[4-(4-fluoro-phenoxy)-phenoxy]-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-139B): MS-(+)-ion: M+1=448.2.
E) ({ 7-[4-(4-fluoro-phenoxy)-phenoxy]-4-hydroxyl-isoquinoline 99.9-3-carbonyl }-amino)-acetate
Be similar to instance D-37e), (Compound D-139A) begins to prepare title product by 7-[4-(4-fluoro-phenoxy)-phenoxy]-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester.MS-(-)-ion: M-1=447.1.
Instance D-140
({ 6-[4-(4-fluoro-phenoxy)-phenoxy]-4-hydroxyl-isoquinoline 99.9-3-carbonyl }-amino)-acetate
A) ({ 7-[4-(4-fluoro-phenoxy)-phenoxy]-4-hydroxyl-isoquinoline 99.9-3-carbonyl }-amino)-acetate
Be similar to instance D-37e), (Compound D-139B) begins to prepare title product by 6-[4-(4-fluoro-phenoxy)-phenoxy]-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester.MS-(-)-ion: M-1=447.1.
Instance D-141
{ [7-(3-chloro-4-fluoro-phenoxy)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate
A) 5-(3-fluoro-4-fluoro-phenoxy)-isoindole-1, the 3-diketone
Be similar to instance D-133a) prepare title product.MS-(-)-ion: M-1=290.5.
B) [5-(3-fluoro--4-fluoro-phenoxy)-1,3-dioxy-1,3-dihydro-isoindole-2-yl]-methyl acetate
Be similar to instance D-133b) prepare title product. 1H?NMR(200MHz,CDC1 3)δ7.83(d,J=8.2Hz,1H),7.32-7.14(m,4H),6.99(m,1H),4.42(s,2H),3.77(s,3H)。
C) 6-and 7-(3-chloro-4-fluoro-phenoxy)-1,4-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance D-1d) prepare.Two kinds of mixture of isomers.MS-(-)-ion: M-1=404.1.
D) 1-chloro-7-(3-chloro-4-fluoro-phenoxy)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance D-137c) prepare.Two kinds of mixture of isomers.MS-(-)-ion: M-1=422.2.
E) 6-and 7-(3-chloro-4-fluoro-phenoxy)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance D-1f) prepare.Separate two kinds of isomer produce 7-(3-chloro-4-fluoro-phenoxy)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-141A): 1H NMR (200MHz, CDC1 3) δ 11.91 (s, 1H), 8.64 (s, 1H), 8.38 (d, J=9.0Hz, 1H), 7.46 (d, J=9.4; 1H), 7.24-7.16 (m, 3H), 7.04-6.98 (m, 1H), 4.50 (t, J=6.8,2H); 1.88 (q, J=7.2,2H), 1.58-1.40 (m, 2H), 0.99 (t, J=7.2,3H); And 6-(3-chloro-4-fluoro-phenoxy)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-141B).MS-(+)-ion: M+1=390.1.
F) { [7-(3,4-two fluoro-phenoxys)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate
Be similar to instance D-37e), by 7-(3-chloro-4-fluoro-phenoxy)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-141A) begin to prepare.MS-(-)-ion: M-1=389.0.
Instance D-142
{ [6-(3-chloro-4-fluoro-phenoxy)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate
A) { [6-(3,4-two fluoro-phenoxys)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate
Be similar to instance D-37e), by 6-(3-chloro-4-fluoro-phenoxy)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-141B) begin to prepare.MS-(-)-ion: M-1=389.0.
Instance D-143
{ [7-(4-chloro-phenoxy)-4-hydroxyl-1-methyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate
A) 6-and 7-(4-chloro-phenoxy)-4-hydroxyl-1-methyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance D-87b), begin to prepare by the mixture of 1-chloro-6-and 7-(4-chloro-phenoxy)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (preparing among the instance D-129e).But, omit adjustment pH value.Separate two kinds of isomer and produce 7-(4-chloro-phenoxy)-4-hydroxyl-1-methyl-isoquinoline-3-carboxylic acid butyl ester (compound of instance D-143a): MS-(+)-ion; M-1=386.1 and 6-(4-chloro-phenoxy)-4-hydroxyl-1-methyl-isoquinoline-3-carboxylic acid butyl ester (compound of instance D-143b): MS-(+)-ion, M-1=386.1.
B) { [7-(4-chloro-phenoxy)-4-hydroxyl-1-methyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate
Be similar to instance D-37e), by the beginning of 7-(4-chloro-phenoxy)-4-hydroxyl-1-methyl-isoquinoline-3-carboxylic acid butyl ester (compound of instance D-143a) and in pressure tube, prepare whole night in 90 ℃ of reactions.MS-(-)-ion M-1=385.0.
Instance D-144
{ [6-(4-chloro-phenoxy)-4-hydroxyl-1-methyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate
A) { [6-(4-chloro-phenoxy)-4-hydroxyl-1-methyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate
Be similar to instance D-37e), by the beginning of 6-(4-chloro-phenoxy)-4-hydroxyl-1-methyl-isoquinoline-3-carboxylic acid butyl ester (compound of instance D-143b) and in pressure tube, prepare whole night in 90 ℃ of reactions.MS-(-)-ion M-1=385.0.
Instance D-145
{ [7-(3,5-two fluoro-phenoxys)-4-hydroxyl-1-methyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate
A) 6-and 7-(3,5-two fluoro-phenoxys)-4-hydroxyl-1-methyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance D-87b), begin to prepare by the mixture of 1-chloro-6-and 7-(3,5-two fluoro-phenoxys)-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (preparing among the instance D-137c).The different slightly adjustment that have been to omit the pH value of handling procedure.Separate two kinds of isomer and produce 7-(3; 5-two fluoro-phenoxys)-and 4-hydroxyl-1-methyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-145a1): MS-(-)-ion; M-1=386.3 and 6-(3; 5-two fluoro-phenoxys)-and 4-hydroxyl-1-methyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-145a2): MS-(-)-ion, M-1=386.3.
B) { [7-(3,5-two fluoro-phenoxys)-4-hydroxyl-1-methyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate
Be similar to instance D-37e), (beginning of Compound D-145a1) also prepares in 90 ℃ of reactions in pressure tube whole night by 7-(3,5-two fluoro-phenoxys)-4-hydroxyl-1-methyl-isoquinoline-3-carboxylic acid butyl ester.MS-(-)-ion M-1=387.1.
Instance D-146
{ [4-hydroxyl-7-(4-methoxyl group-phenoxy)-1-methyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate
A.6-and 7-(4-methoxyl group-phenoxy)-1-bromo-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
In microwave reactor (ST) in 130 ℃ of heating 6-and 7-(4-methoxyl group-phenoxy)-1,4-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-88d) (3.0g) and the mixture 15min of bromine phosphorus oxide (3.4g) in dry toluene (40ml).After cooling, concentrated reaction mixture also adds saturated sodium bicarbonate aqueous solution (100ml).Stir 20min also then with ETHYLE ACETATE (2 * 100ml) extractions.To merge organic layer water, salt solution cleaning, via dried over mgso, filtration and concentrated to produce title compound (3.1g).MS-(+)-ion M+1=446.05,448.05.
B.6-and 7-(4-methoxyl group-phenoxy)-4-hydroxyl-1-methyl-isoquinoline-3-carboxylic acid butyl ester
In microwave reactor (ST) in 120 ℃ of heating 6-and 7-(4-methoxyl group-phenoxy)-1-bromo-4-hydroxyl-isoquinoline-3-carboxylic acid butyl esters (232mg), Pd (PPh 3) 4(60mg), trimethylboroxin (65mg) and the mixture 10min of salt of wormwood (216mg) in dioxane (4ml).After the cooling, water (15ml) diluted reaction mixture.Be acidified to pH=4 with 2N HCl.Use ethyl acetate extraction.Clean organic layer with salt solution, via dried over mgso and filtration.Concentrating filtrate also separates with generation 7-(4-methoxyl group-phenoxy)-4-hydroxyl-1-methyl-isoquinoline-3-carboxylic acid butyl ester (35mg) ((MS-(+)-ion M+1=382.18) and 6-(4-methoxyl group-phenoxy)-4-hydroxyl-1-methyl-isoquinoline-3-carboxylic acid butyl ester (61mg) (Compound D-146b2) (MS-(+)-ion M+1=382.16) of Compound D-146b1) through silica gel chromatography (with 25% to 50% eluent ethyl acetate in the hexane).
C) { [4-hydroxyl-7-(4-methoxyl group-phenoxy)-1-methyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate
Be similar to instance D-107b), by 7-(4-methoxyl group-phenoxy)-4-hydroxyl-1-methyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-146b1) preparation (120 ℃ of microwave reaction temperature, reaction times 10min).MS-(-)-ion M-1=381.09.
Instance D-147
{ [4-hydroxyl-6-(4-methoxyl group-phenoxy)-1-methyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate
Be similar to instance D-146c), by 6-(4-methoxyl group-phenoxy)-4-hydroxyl-1-methyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-146b2) preparation.MS-(-)-ion: M-1=381.10.
Instance D-148
[(6-cyclohexyloxy-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
A. (5-hydroxyl-1,3-dioxy-1,3-dihydro-isoindole-2-yl)-ETHYLE ACETATE
Be similar to instance D-100c), by 4-hydroxyl-phthalic acid and glycine ethyl ester hydrochloride preparation. 1H?NMR(200MHz,DMSO-d 6)δ11.0(br?s,1H),7.74(d,J=7.8Hz,1H),7.17(m,2H),4.35(s,2H),4.13(q,J=7.0Hz,2H),1.20(t,J=7.0Hz,3H)。
B. (5-cyclohexyloxy-1,3-dioxy-1,3-dihydro-isoindole-2-yl)-ETHYLE ACETATE
Hexalin (3.2g), diethyl azodiformate (6.9g) are added into (5-hydroxyl-1; 3-dioxy-1,3-dihydro-isoindole-2-yl)-mixture of ETHYLE ACETATE (8.0g) in anhydrous tetrahydro furan (160ml) in and then add triphenylphosphine (12.6g).At room temperature stir gained mixture and concentrated whole night.Resistates is divided between water and ETHYLE ACETATE to be dissolved.Use the ethyl acetate extraction water layer.Clean the merging organic phase with salt solution, via dried over mgso and filtration.Concentrating filtrate also passes through silica gel chromatography (with 5% eluent ethyl acetate in the methylene dichloride) purifying to produce title compound (6.2g). 1H?NMR(200MHz,CDC1 3)δ7.73(dd,J=8.2,0.8Hz,1H),7.30(br?s,1H),7.12(m,1H),4.38(m,3H),4.21(q,J=7.1Hz,2H),2.02(m,2H),1.82-1.25(m,13H)。
C.6-with 7-cyclohexyloxy-1,4-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance D-1d) prepare; Produce 7-cyclohexyloxy-1; 4-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-148c1) (MS-(+)-ion M+1=360.16) and 6-cyclohexyloxy-1,4-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-148c2) (MS-(+)-ion M+1=360.18).
D.1-bromo-6-cyclohexyloxy-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance D-146a), by 6-cyclohexyloxy-1,4-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-148c2) preparation.MS-(+)-ion M+1=422.10,424.10.
E.6-cyclohexyloxy-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
10%Pd/C (50% wet) (460mg) is added in the l-bromo-6-cyclohexyloxy-4-hydroxyl-mixture of isoquinoline-3-carboxylic acid butyl ester (1.0g) in ETHYLE ACETATE (20ml) and then adds ammonium formiate (1.5g).Backflow gained mixture 4h.After the cooling, filter reaction mixture also concentrates.Through silica gel chromatography (the 5%-10% ETHYLE ACETATE in the methylene dichloride) purifying resistates to produce title compound (640mg).MS-(+)-ion M+1=344.22.
F. [(6-cyclohexyloxy-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
Be similar to instance D-146c) prepare.MS-(-)-ion M-1=343.15.
Instance D-149
[(7-cyclohexyloxy-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
A.1-bromo-7-cyclohexyloxy-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance D-146a), by 7-cyclohexyloxy-1,4-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-148c1) prepare.MS-(+)-ion M+1=422.12,424.12.
B.7-cyclohexyloxy-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance D-148e) prepare.MS-(+)-ion M+1=344.22.
C. [(7-cyclohexyloxy-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
Be similar to instance D-146c) prepare.MS-(-)-ion M-1=343.17.
Instance D-150
[(7-cyclohexyloxy-4-hydroxyl-1-methyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
A.7-cyclohexyloxy-4-hydroxyl-1-methyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance D-146b) prepare.MS-(+)-ion M+1=358.21.
B. [(7-cyclohexyloxy-4-hydroxyl-1-methyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
Be similar to instance D-146c) prepare.MS-(+)-ion M+1=359.15.
Instance D-151
[(7-hexamethylene sulfenyl-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
A. (5-hexamethylene sulfenyl-1,3-dioxy-1,3-dihydro-isoindole-2-yl)-ETHYLE ACETATE
With 5-nitro-isoindole-1,3-diketone (10.0g), hexanaphthene mercaptan (9.1g) and the mixture heating up of salt of wormwood (18.7g) in acetone (260ml) are to refluxing whole night.After the cooling, water (250ml) dilutes this mixture and then is acidified to pH=4 with 6N HCl.Collecting precipitation thing and dried in vacuum are to produce midbody 5-hexamethylene sulfenyl-isoindole-1,3-diketone (15.6g).This midbody is dissolved in the acetone (170mg) and METHYL BROMOACETATE (10.6g) and salt of wormwood (23.8g) are added so far in the mixture.Reflux this mixture whole night.After the cooling, filter reaction mixture is also used rinsed.Concentrating filtrate also passes through silica gel chromatography (the 10%-50% ETHYLE ACETATE in the methylene dichloride) purifying to produce title compound (13.1g). 1HNMR(200MHz,CDC1 3)δ7.73(m,2H),7.56(dd,J=7.8,1.6Hz,1H),4.40(s,2H),4.21(q,J=7.0Hz,2H),3.37(m,1H),2.07-1.28(m,13H)。
B.6-with 7-hexamethylene sulfenyl-1,4-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance D-21b) prepare.MS-(+)-ion M+1=376.20.
C.6-with 7-hexamethylene sulfenyl-1-chloro-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Heating in microwave reactor (ST) (180 ℃, 30min) 6-and 7-hexamethylene sulfenyl-1,4-dihydroxyl-isoquinoline-3-carboxylic acid butyl ester (1.0g) and the mixture of phosphorus oxychloride (491mg) in dry toluene (14ml).After the cooling, make the reaction mixture quenching with saturated sodium bicarbonate.At stirring at room 20min and with ethyl acetate extraction 2 times.To merge organic layer water, salt solution cleaning, via dried over mgso, filtration and concentrated to produce title compound (0.5g).MS-(+)-ion M+1=394.12.
D.6-with 7-hexamethylene sulfenyl-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance D-1f) prepare, produce 7-hexamethylene sulfenyl-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (128mg) ((MS-(+)-ion M+1=360.15) and 6-hexamethylene sulfenyl-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (130mg) (Compound D-151d2) (MS-(+)-ion M+1=360.17) of Compound D-151d1).
E) [(7-hexamethylene sulfenyl-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
Be similar to instance D-1g), by 7-hexamethylene sulfenyl-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-151d1) prepare.MS-(-)-ion M-1=359.11.
Instance D-152
[(7-hexamethylene alkylsulfonyl-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
A) 7-hexamethylene alkylsulfonyl-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester
With 7-hexamethylene sulfenyl-4-hydroxyl-isoquinoline-3-carboxylic acid butyl ester (Compound D-151d1) (64mg) and-mixture of chlorine peroxybenzoic acid (111mg) in methylene dichloride (2ml) stirred overnight at room temperature.With its with methylene dichloride (50ml) dilution and use successively saturated sodium bicarbonate aqueous solution (2 * 50ml), water and salt solution cleans.Via dried over mgso organic layer and filtration.Concentrating filtrate also passes through silica gel chromatography (with the 3%-15% eluent ethyl acetate in the methylene dichloride) purifying to produce title compound (70mg).MS-(+)-ion M+1=392.20.
B. [(7-hexamethylene alkylsulfonyl-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
Be similar to instance D-146c) prepare.MS-(-)-ion M-1=391.05.
Instance D-153
[(4-hydroxyl-1-isobutyl--isoquinoline 99.9-3-carbonyl)-amino]-acetate
A.4-benzyloxy-1-isobutyl--isoquinoline-3-carboxylic acid butyl ester
4-benzyloxy-1-bromo-isoquinoline-3-carboxylic acid butyl ester (207mg, 0.5mmol see instance D-86a), Pd (PPh under agitation reflux 3) 4(58mg, 0.05mmol), 2-methyl-propyl boric acid (78mg, 0.75mmol), K 2CO 3(207mg, 1.5mmol) with 1, the mixture 48h of 4-dioxane (4ml).Concentrate this mixture subsequently in a vacuum.Water (5ml) is added in the resistates and (2 * 20ml) extract this mixture with EtOAc.Via MgSO 4Dry organic phase and evaporation in a vacuum.On silica gel, use hexane: EtOAc=88 through flash column chromatography: 12 come the purifying resistates as elutriant, produce the title compound (136mg) that is little yellow oil; MS-(+)-ion: M+1=392.3.
B) 4-hydroxyl-1-isobutyl--isoquinoline-3-carboxylic acid butyl ester
At H 2Under environmental stress and temperature, stir under-the atmosphere 4-benzyloxy-1-isobutyl--isoquinoline-3-carboxylic acid butyl ester (125mg, 0.32mmol), the mixture 24h of Pd/C (50mg, Aldrich, 10 weight %Pd) and EtOAc (15ml).Then filter this mixture through Celite pad.Concentrating filtrate and obtain being the title compound (87mg) of little yellow oil in a vacuum; MS-(+)-ion M+1=302.2.
C) [(4-hydroxyl-1-isobutyl--isoquinoline 99.9-3-carbonyl)-amino]-acetate
Be similar to instance D-1g), synthetic by 4-hydroxyl-1-isobutyl--isoquinoline-3-carboxylic acid butyl ester; MS-(+)-ion: M+1=303.2.
Instance D-154
[(4-hydroxyl-1-pyridine-2-base-isoquinoline 99.9-3-carbonyl)-amino]-acetate
A.4-benzyloxy-1-pyridine-2-base-isoquinoline-3-carboxylic acid butyl ester
In succession with toluene (15mml), 4-benzyloxy-1-bromo-isoquinoline-3-carboxylic acid butyl ester (1.035mg, 2.5mmol see instance D-86a), Pd (PPh 3) 4(292mg is 0.25mmol) with 2M Na 2CO 3(2.5ml, (323mg is in EtOH 2.5mmol) (2.5ml) solution 5mmol) to be added into pyridine-2-ylboronic acid for the aqueous solution.Then at N 2Protection is this mixture of stirring and refluxing 24h down.Subsequently, concentrate this mixture in a vacuum.Water (15ml) is added in the resistates and extracts this mixture with EtOAc (30ml).Via MgSO 4Dry organic phase and evaporation in a vacuum.On silica gel, use CH through flash column chromatography 2Cl 2: MeOH=98: 2 come the purifying resistates as elutriant, produce black oil, and it uses CH through flash column chromatography on silica gel 2Cl 2: MeOH=99: 1 is further purified as elutriant, and uses CH through preparation TLC subsequently 2Cl 2: MeOH=98: 2 produce the title compound (19mg) that is yellow oil as elutriant (must repeated several times); MS-(+)-ion M+1=413.2.
B) 4-hydroxyl-1-pyridine-2-base-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance D-153b), synthetic by 4-benzyloxy-1-pyridine-2-base-isoquinoline-3-carboxylic acid butyl ester; MS-(-)-ion: M-1=321.4.
C) [(4-hydroxyl-1-pyridine-2-base-isoquinoline 99.9-3-carbonyl)-amino]-acetate
Be similar to instance D-1g), synthetic by 4-hydroxyl-1-pyridine-2-base-isoquinoline-3-carboxylic acid butyl ester; MS-(+)-ion: M+1=324.1.
Instance D-155
[(1-ethyl-4-hydroxyl-7-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-acetate
A) 4-hydroxyl-7-phenoxy-1-vinyl-isoquinoline-3-carboxylic acid butyl ester
At N 2Protection is stirring and refluxing 1-bromo-4-hydroxyl-7-phenoxy-isoquinoline-3-carboxylic acid butyl ester (416mg, 1mmol see instance D-28a), Pd (PPh down 3) 4(118mg, 0.1mmol), 2,4,6-triethylene basic ring three boroxanes-pyridine complex (241mg, 1mmol), K 2CO 3(414mg, 3mmol) with 1, the mixture 3h of 4-dioxane (8ml).Concentrate this mixture subsequently in a vacuum.Water (5ml) is added in the resistates and extracts this mixture with EtOAc (20ml).Via MgSO 4Dry organic phase and evaporation in a vacuum.On silica gel, use hexane: EtOAc=98 through flash column chromatography: 2 come the purifying resistates as elutriant, produce the title compound (65mg) that is little yellow solid; MS-(+)-ion: M+1=364.1.
B) 1-ethyl-4-hydroxyl-7-phenoxy-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance D-153b), synthetic by 4-hydroxyl-7-phenoxy-1-vinyl-isoquinoline-3-carboxylic acid butyl ester; MS-(+)-ion: M+1=366.1.
C) [(1-ethyl-4-hydroxyl-7-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-acetate
Be similar to instance D-1g), synthetic by 1-ethyl-4-hydroxyl-7-phenoxy-isoquinoline-3-carboxylic acid butyl ester; MS-(+)-ion: M+1=367.1.
Instance D-156
[(1-dimethylamino methyl-4-hydroxyl-7-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
A.1-dimethylamino methyl-4-hydroxyl-7-phenyl sulfenyl-isoquinoline-3-carboxylic acid butyl ester
Stir 4-hydroxyl-7-phenyl sulfenyl-isoquinoline-3-carboxylic acid butyl ester (177mg, 0.5mmol at ambient temperature; See instance D-1f), iodate N, N-dimethylated methylene base ammonium (94mg, 0.5mmol), K 2CO 3(104mg is 0.75mmol) with anhydrous CH 2Cl 2Mixture (3ml) 2.5 days concentrates this mixture then in a vacuum.(15ml) is added in the resistates with water, comes this mixture of acidifying and then uses Et through adding the 6N HCl aqueous solution 2(3 * 30ml) clean O.Subsequently through adding dense NaHCO 3Neutralize this mixture and of the aqueous solution with EtOAc extraction (20ml).Via MgSO 4Dry organic phase also concentrates to produce the title compound (34mg) of black in color oil in a vacuum; MS-(+)-ion: M+1=411.1.
B) [(1-dimethylamino methyl-4-hydroxyl-7-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
Be similar to instance D-1g), synthetic by 1-dimethylamino methyl-4-hydroxyl-7-phenyl sulfenyl-isoquinoline-3-carboxylic acid butyl ester; MS-(+)-ion: M+1=412.0.
Instance D-157
[(4-hydroxyl-1-methyl-7-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
A) 1-bromo-4-hydroxyl-7-phenyl sulfenyl-isoquinoline-3-carboxylic acid
Stir 1 in the 600ml anhydrous acetonitrile, 4-dihydroxyl-7-phenyl sulfenyl-isoquinoline-3-carboxylic acid butyl ester (instance D-1d) compd A down refluxing) (29.0g) and bromine phosphorus oxide (67.5g) 4 hours.After cooling, concentrated reaction mixture also is added into saturated sodium bicarbonate solution and ETHYLE ACETATE in the resistates and stirs whole night.The throw out and the water that are collected in interlayer formation clean to produce title compound (10.2g).MS-(+)-ion M+1=376.0,378.1.
B) 1-bromo-4-hydroxyl-7-phenyl sulfenyl-isoquinoline-3-carboxylic acid methyl esters
Be suspended in the 500ml acetone 1-bromo-4-hydroxyl-7-phenyl sulfenyl-isoquinoline-3-carboxylic acid (10.0g), salt of wormwood (3.7g) and methyl-sulfate (3.4g) and stirred overnight under refluxing.Concentrated reaction mixture also divides resistates to dissolve between 1N hydrochloric acid and ETHYLE ACETATE.Via dried over mgso organic layer and filtration.Concentrating filtrate is to produce title compound (9.6g).MS-(+)-ion M+1=389.9,391.9.
C) 4-hydroxyl-1-methyl-7-phenyl sulfenyl-isoquinoline-3-carboxylic acid methyl esters
In microwave reactor (ST), heat 1,1-bromo-4-hydroxyl-7-phenyl sulfenyl-isoquinoline-3-carboxylic acid methyl esters (0.2g), tetrakis triphenylphosphine palladium (60mg), trimethylboroxin (65mg) and salt of wormwood 10min in the 4-dioxane (4ml) in 140 ℃.After cooling, concentrated reaction mixture also divides molten between 1N hydrochloric acid and ETHYLE ACETATE.Via dried over mgso organic layer and filtration.Concentrating filtrate also passes through silica gel chromatography (with 2% eluent ethyl acetate in the methylene dichloride) and separates to produce title compound (47mg).MS-(+)-ion M+1=326.1.
D) [(4-hydroxyl-1-methyl-7-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate
Be similar to instance D-146c) prepare.MS-(+)-ion M+1=369.1.
Instance D-158
{ [4-hydroxyl-1-methyl-7-(4-trifluoromethyl-phenoxy)-isoquinoline 99.9-3-carbonyl]-amino }-acetate
A.4-hydroxyl-1-methyl-7-(4-trifluoromethyl-phenoxy)-isoquinoline-3-carboxylic acid butyl ester
Be similar to instance D-157d), prepare by 4-hydroxyl-1-chloro-7-(4-trifluoromethyl-phenoxy)-isoquinoline-3-carboxylic acid butyl ester (instance D-92f).MS-(+)-ion M+1=420.2.
B) { [4-hydroxyl-1-methyl-7-(4-trifluoromethyl-phenoxy)-isoquinoline 99.9-3-carbonyl]-amino }-acetate
Be similar to instance D-146c) prepare.MS-(+)-ion M+1=421.2.

Claims (14)

1. compound that is expressed from the next:
Wherein:
R 1Be selected from the group that forms by following each base: hydrogen; Halogen; Alkyl; Through substituted alkyl; Alkoxyl group; Through substituted alkoxy; Amino; Through substituted-amino; Aminoacyl; Aryl; Through substituted aryl; Heteroaryl; Through substituted heteroaryl; Heterocycle; Through substituted heterocycle; And-XR 6, wherein X be oxygen ,-S (O) n-or-NR 7-, wherein n is 0,1 or 2, R 6Be selected from by following each group of forming of base: alkyl, through substituted alkyl, aryl, through substituted aryl, heteroaryl, through substituted heteroaryl, heterocycle with through substituted heterocycle, and R 7Be hydrogen, alkyl or aryl, perhaps as X be-NR 7-time, R 7And R 6Can be connected to form heterocycle or through substituted heterocyclic radical together with its bonded nitrogen-atoms; And
R 2Be selected from the group that forms by following each base: hydrogen; Alkyl; Through substituted alkyl; Aryl; Through substituted aryl; Heteroaryl; Through substituted heteroaryl; Halogen; Hydroxyl; Cyanic acid;-S (O) n-N (R 6)-R 6, wherein n is 0,1 or 2;-NR 6C (O) NR 6R 6-XR 6, wherein X be oxygen ,-S (O) n-or-NR 7-, wherein n is 0,1 or 2, each R 6Independently be selected from by hydrogen, alkyl, through substituted alkyl, aryl, through substituted aryl, naphthenic base, through substituted cycloalkyl, heteroaryl, through substituted heteroaryl, heterocycle and the group that forms through substituted heterocycle, restricted condition for as X be-SO-or-SO 2-time, R 6Be not hydrogen, and R 7Be selected from the group that forms by hydrogen, alkyl, aryl, perhaps R 2, R 3Form through the substituted aryl of aryl, heteroaryl or through substituted heteroaryl together with side joint carbon atom on it;
Or its pharmaceutically acceptable salt, ester or prodrug;
At least a situation below restricted condition is to take place:
1) R 1Be fluorine; Bromine; Iodine; Alkyl; Through substituted alkyl; Alkoxyl group; Aminoacyl; Through substituted alkoxy; Aryl; Through substituted aryl; Heteroaryl; Through substituted heteroaryl; Heterocycle; Through substituted heterocycle; And-XR 6, wherein X be oxygen ,-S (O) n-or-NR 7-, wherein n is 0,1 or 2, R 6Be selected from by alkyl, through substituted alkyl, aryl, through substituted aryl, heteroaryl, through substituted heteroaryl, heterocycle and the group that forms through substituted heterocycle, and R 7Be hydrogen, alkyl or aryl; Perhaps
2) R 2For through substituted alkyl; Aryl; Through substituted aryl; Heteroaryl; Through substituted heteroaryl; Fluorine; Iodine; Cyanic acid;-XR 6, wherein X be oxygen ,-S (O) n-or-NR 7-, wherein n is 0,1 or 2, R 6Be selected from by alkyl, through substituted alkyl, aryl, through substituted aryl, heteroaryl, through substituted heteroaryl, heterocycle and the group that forms through substituted heterocycle, and R 7Be hydrogen, alkyl or aryl, restricted condition is:
A) work as R 2For when the substituted alkyl, said substituting group does not comprise trifluoromethyl;
B)-XR 6It is not alkoxyl group; With
C) as-XR 6For when the substituted alkoxy, said substituting group does not comprise benzyl or through being selected from by (C 1-C 5) alkyl and (C 1-C 5) group that forms of alkoxyl group the substituted benzyl of substituting group or do not comprise the fluoroalkyl substituting group of following formula:
-O-[CH 2] x-C fH (2f+1-g)F g
Wherein x is 0 or 1; F is 1 to 5 integer; And g is 1 integer to (2f+1).
2. compound that is selected from the group that forms by following material:
{ [4-hydroxyl-1-(naphthalene-2-base oxygen base)-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
{ [4-hydroxyl-1-(pyridin-3-yl oxygen base)-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
{ [4-hydroxyl-1-(4-methoxyl group-phenoxy)-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
{ [4-hydroxyl-1-(3-methoxyl group-phenoxy)-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
{ [1-(3-fluoro-phenoxy)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
{ [1-(4-fluoro-phenoxy)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
{ [1-(2-fluoro-phenoxy)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
{ [4-hydroxyl-1-(2-methoxyl group-phenoxy)-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
{ [1-(4-acetylaminohydroxyphenylarsonic acid phenoxy)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
{ [4-hydroxyl-1-(4-methanesulfonamido-phenoxy)-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
[(4-hydroxyl-1-phenyl amino-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
{ [4-hydroxyl-7-(pyridin-3-yl oxygen base)-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
[(4-hydroxyl-1-methoxyl group-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(1-oxyethyl group-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(4-hydroxyl-1-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(4-hydroxyl-1-methyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(4-hydroxyl-1-methoxymethyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(1-dimethylamino formyl radical-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(4-hydroxyl-1-methyl-7-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(1-dimethylamino formyl radical-4-hydroxyl-7-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(4-hydroxyl-1-methoxymethyl-7-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(4-hydroxyl-1-right-tolyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
{ [7-(4-fluoro-phenoxy)-4-hydroxyl-1-methyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
{ [1-chloro-4-hydroxyl-7-(4-methoxyl group-phenoxy)-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
{ [4-hydroxyl-7-(4-methoxyl group-phenoxy)-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
{ [1-chloro-4-hydroxyl-7-(4-trifluoromethyl-phenoxy)-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
{ [4-hydroxyl-7-(4-trifluoromethyl-phenoxy)-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
{ [1-chloro-7-(4-fluoro-phenoxy)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
{ [7-(4-fluoro-phenoxy)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
{ [4-hydroxyl-7-(pyridin-4-yl sulfenyl)-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
[(7-benzenesulfinyl-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(7-benzenesulfonyl-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
{ [4-hydroxyl-7-(4-methoxyl group-phenylsulfonamido)-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
{ [4-hydroxyl-7-(3-phenyl-urea groups)-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
[(4-hydroxyl-1-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
{ [1-(4-chloro-phenyl sulfenyl)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
[(4-hydroxyl-1-right-tolyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
{ [4-hydroxyl-1-(pyridine-2-base sulfenyl)-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
{ [4-hydroxyl-1-(3-methoxyl group-phenyl sulfenyl)-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
{ [4-hydroxyl-1-(2-methoxyl group-phenyl sulfenyl)-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
{ [4-hydroxyl-1-(naphthalene-2-base sulfenyl)-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
[(1-benzenesulfinyl-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(1-benzenesulfonyl-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
{ [4-hydroxyl-7-(pyridine-2-base sulfenyl)-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
({ 4-hydroxyl-7-[4-(toluene-4-sulfuryl amino)-phenoxy]-isoquinoline 99.9-3-carbonyl }-amino)-acetate;
{ [4-hydroxyl-7-(4-nitro-phenoxy)-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
{ [7-(4-phenylsulfonamido-phenoxy)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
{ [4-hydroxyl-7-(4-methanesulfonamido-phenoxy)-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
{ [7-(4-chloro-phenoxy)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
{ [7-(3-fluoro-5-methoxyl group-phenoxy)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
{ [7-(3,4-two fluoro-phenoxys)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
{ [4-hydroxyl-7-(4-trifluoromethoxy-phenoxy)-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
[(4-hydroxyl-7-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(1-chloro-4-hydroxyl-7-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(1-bromo-4-hydroxyl-7-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(4-hydroxyl-7-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(1-chloro-4-hydroxyl-7-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(1-bromo-4-hydroxyl-7-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
{ [7-(2,6-dimethyl--phenoxy)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
{ [1-chloro-7-(2,6-dimethyl--phenoxy)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
{ [1-bromo-7-(2,6-dimethyl--phenoxy)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
[(1-bromo-7-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(1-bromo-4-hydroxyl-7-trifluoromethyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(4-hydroxyl-1-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(1,7-two bromo-4-hydroxyl-isoquinoline 99.9-3-carbonyls)-amino]-acetate;
[(7-bromo-1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(1-bromo-7-fluoro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(7-fluoro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(1-chloro-7-fluoro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(1-bromo-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(4-hydroxyl-7-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(1-chloro-4-hydroxyl-7-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(1-bromo-4-hydroxyl-7-phenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(1-ethyl sulfenyl-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
{ [4-hydroxyl-1-(4-methoxyl group-phenyl sulfenyl)-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
[(1-chloro-4-hydroxyl-7-iodo-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(4-hydroxyl-7-iodo-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(1-bromo-4-hydroxyl-7-methyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(1-bromo-7-butoxy-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(1-chloro-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-methyl-amino]-acetate;
[(1-chloro-4-hydroxyl-7-isopropoxy-isoquinoline 99.9-3-carbonyl)-methyl-amino]-acetate;
{ [7-(3,5-two fluoro-phenoxys)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
({ 7-[4-(4-fluoro-phenoxy)-phenoxy]-4-hydroxyl-isoquinoline 99.9-3-carbonyl }-amino)-acetate;
{ [7-(3-chloro-4-fluoro-phenoxy)-4-hydroxyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
{ [7-(4-chloro-phenoxy)-4-hydroxyl-1-methyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
{ [7-(3,5-two fluoro-phenoxys)-4-hydroxyl-1-methyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
{ [4-hydroxyl-7-(4-methoxyl group-phenoxy)-1-methyl-isoquinoline 99.9-3-carbonyl]-amino }-acetate;
[(7-cyclohexyl oxygen base-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(7-cyclohexyl oxygen base-4-hydroxyl-1-methyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(7-cyclohexyl sulfenyl-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(7-hexamethylene alkylsulfonyl-4-hydroxyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(4-hydroxyl-1-isobutyl--isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(4-hydroxyl-1-pyridine-2-base-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(1-ethyl-4-hydroxyl-7-phenoxy-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(1-dimethylamino methyl-4-hydroxyl-7-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
[(4-hydroxyl-1-methyl-7-phenyl sulfenyl-isoquinoline 99.9-3-carbonyl)-amino]-acetate;
{ [4-hydroxyl-1-methyl-7-(4-trifluoromethyl-phenoxy)-isoquinoline 99.9-3-carbonyl]-amino }-acetate.
3. the compound of a following formula:
Figure FDA00001645958300051
Or its pharmaceutically acceptable salt, ester or prodrug.
4. the compound of a following formula:
Figure FDA00001645958300061
Or its pharmaceutically acceptable salt, ester or prodrug.
5. the compound of a following formula:
Figure FDA00001645958300062
Or its pharmaceutically acceptable salt, ester or prodrug.
6. the compound of a following formula:
Figure FDA00001645958300063
Or its pharmaceutically acceptable salt, ester or prodrug.
7. the compound of a following formula:
Figure FDA00001645958300064
Or its pharmaceutically acceptable salt, ester or prodrug.
8. the compound of a following formula:
Figure FDA00001645958300071
Or its pharmaceutically acceptable salt, ester or prodrug.
9. the compound of a following formula:
Figure FDA00001645958300072
Or its pharmaceutically acceptable salt, ester or prodrug.
10. the compound of a following formula:
Figure FDA00001645958300073
Or its pharmaceutically acceptable salt, ester or prodrug.
11. the compound of a following formula:
Figure FDA00001645958300074
Or its pharmaceutically acceptable salt, ester or prodrug.
12. the compound of a following formula:
Figure FDA00001645958300075
Or its pharmaceutically acceptable salt, ester or prodrug.
13. the compound of a following formula:
Or its pharmaceutically acceptable salt, ester or prodrug.
14. the compound of a following formula:
Figure FDA00001645958300082
Or its pharmaceutically acceptable salt, ester or prodrug.
CN2012101526867A 2003-06-06 2004-06-04 Novel nitrogen-containing heteroaryl compounds and methods of use thereof Pending CN102718708A (en)

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